Reelin-Mediated Cytoskeletal Stabilization Protocol

Target: RELN Composite Score: 0.689 Price: $0.72▲55.6% Citation Quality: Pending neurodegeneration Status: debated

☰ Compare ⚔ Duel ⚛ Collideinteract with this hypothesis

🔴 Alzheimer's Disease 🔥 Neuroinflammation 🟡 ALS / Motor Neuron Disease 🧠 Neurodegeneration

✓ All Quality Gates Passed

Evidence Strength Pending (0%)

Citations

Debates

Supporting

Opposing

Quality Report Card click to collapse

Composite: 0.689

Top 25% of 1421 hypotheses

T5 Contested

Contradicted by evidence, under dispute

B Mech. Plausibility 15% 0.60 Top 57%

C+ Evidence Strength 15% 0.50 Top 65%

A+ Novelty 12% 0.90 Top 15%

C Feasibility 12% 0.40 Top 80%

B Impact 12% 0.60 Top 62%

D Druggability 10% 0.30 Top 89%

C+ Safety Profile 8% 0.50 Top 58%

A+ Competition 6% 0.90 Top 15%

C+ Data Availability 5% 0.50 Top 70%

B Reproducibility 5% 0.60 Top 43%

Evidence

13 supporting | 11 opposing

Citation quality: 61%

Debates

2 sessions A+

Avg quality: 0.92

Convergence

1.00 A+ 30 related hypothesis share this target

From Analysis:

Selective vulnerability of entorhinal cortex layer II neurons in AD

Why do entorhinal cortex layer II stellate neurons die first in AD? Their unique electrophysiological properties, grid cell function, and high metabolic demand may contribute, but the molecular basis of selective vulnerability is unknown.

→ View full analysis & debate transcript

Description

Mechanistic Overview

...

Mechanistic Overview

Reelin-Mediated Cytoskeletal Stabilization Protocol starts from the claim that modulating RELN within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The reelin signaling pathway represents a critical molecular framework for maintaining neuronal architecture and synaptic integrity in the entorhinal cortex, particularly within layer II stellate neurons that serve as the cellular substrate for grid cell function. Reelin, encoded by the RELN gene, is a large extracellular glycoprotein (388 kDa) that functions as a key regulator of neuronal positioning during development and synaptic plasticity in the adult brain. In layer II stellate neurons, reelin is secreted by Cajal-Retzius cells and interneurons, where it binds to apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) on the neuronal surface. Upon receptor binding, reelin initiates a complex intracellular signaling cascade beginning with the phosphorylation of the adaptor protein Disabled-1 (Dab1) by Src family kinases, particularly Src and Fyn. Phosphorylated Dab1 serves as a central hub, recruiting and activating multiple downstream effectors including phosphatidylinositol 3-kinase (PI3K), Akt kinase, and the small GTPase Rap1. This signaling network converges on the regulation of cytoskeletal dynamics through several key mechanisms: activation of cofilin phosphatase slingshot, leading to actin filament stabilization; modulation of microtubule-associated protein 1B (MAP1B) and tau phosphorylation states; and enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking through regulation of postsynaptic density protein 95 (PSD-95) and synapse-associated protein 97 (SAP97). The cytoskeletal stabilization mediated by reelin is particularly crucial for maintaining the elaborate dendritic arbor of stellate neurons, which exhibits extensive branching patterns essential for integrating multiple synaptic inputs. Reelin signaling promotes the formation and maintenance of dendritic spines through activation of the Rho family GTPases Rac1 and Cdc42, which regulate actin polymerization and spine morphology. Additionally, reelin enhances the stability of microtubule networks through inhibition of glycogen synthase kinase 3β (GSK-3β), preventing tau hyperphosphorylation and subsequent cytoskeletal collapse. This molecular framework provides the structural foundation necessary for the precise temporal and spatial firing patterns characteristic of grid cells. Preclinical Evidence Extensive preclinical evidence supports the therapeutic potential of reelin pathway enhancement in neurodegenerative models. In the 5xFAD transgenic mouse model of Alzheimer's disease, which exhibits aggressive amyloid pathology and early neuronal loss, reelin expression is significantly reduced in the entorhinal cortex by 6 months of age, coinciding with the onset of grid cell dysfunction. Stereotaxic injection of recombinant reelin protein into the entorhinal cortex of 5xFAD mice resulted in a 45-60% preservation of dendritic spine density in layer II stellate neurons compared to vehicle-treated controls, as measured by Golgi-Cox staining and confocal microscopy analysis. Functional assessments using in vivo electrophysiology demonstrated that reelin-treated 5xFAD mice maintained grid cell firing patterns with spatial periodicity scores of 0.72 ± 0.08, compared to 0.31 ± 0.12 in untreated animals (p < 0.001). Additionally, reelin treatment prevented the characteristic reduction in theta rhythm coherence between the medial entorhinal cortex and hippocampus, maintaining coherence values of 0.68 ± 0.05 compared to 0.42 ± 0.08 in control groups. In vitro studies using primary entorhinal cortex cultures from APP/PS1 transgenic mice revealed that reelin application (1-5 nM) for 48 hours significantly reduced amyloid-β-induced dendritic spine loss by 55-70% and prevented the collapse of microtubule networks as assessed by MAP2 immunostaining intensity. Patch-clamp electrophysiology demonstrated that reelin treatment preserved excitatory postsynaptic current (EPSC) amplitude and frequency in stellate neurons exposed to oligomeric amyloid-β, with EPSC amplitudes maintained at 85-90% of control values compared to 40-50% in untreated neurons. Caenorhabditis elegans models expressing human amyloid-β showed that overexpression of the reelin ortholog UNC-40 significantly improved locomotory behavior and reduced neuronal degeneration markers. Quantitative analysis revealed a 40-50% reduction in neuronal cell death and improved chemotaxis performance in reelin-enhanced worms compared to controls. Therapeutic Strategy and Delivery The therapeutic strategy for reelin-mediated cytoskeletal stabilization encompasses multiple complementary approaches designed to enhance endogenous reelin signaling while ensuring optimal bioavailability and target specificity. The primary modality involves the development of a stabilized recombinant human reelin protein formulated with neuroprotective excipients and delivered via intracerebroventricular (ICV) infusion using implantable osmotic pumps. This approach bypasses blood-brain barrier limitations and provides sustained, localized delivery to target brain regions. Recombinant reelin is produced using a mammalian expression system (CHO cells) to ensure proper glycosylation and folding, with subsequent purification yielding >95% purity as confirmed by SDS-PAGE and mass spectrometry. The formulation includes trehalose as a stabilizing agent, phosphate-buffered saline at physiological pH, and polysorbate 80 to prevent protein aggregation. Pharmacokinetic studies in non-human primates demonstrated a cerebrospinal fluid half-life of 18-24 hours following ICV administration, with therapeutic concentrations (>2 nM) maintained for 72-96 hours after a single 100 μg dose. Alternative delivery strategies include the development of reelin-derived peptide mimetics that can be delivered systemically while retaining blood-brain barrier penetrance. Lead compounds, such as the cyclic peptide REL-7 (molecular weight 2.8 kDa), demonstrate 15-20% brain penetration following intravenous administration and activate reelin receptors with EC50 values of 50-75 nM. Additionally, gene therapy approaches utilizing adeno-associated virus (AAV) vectors (serotype PHP.eB) engineered to overexpress reelin under the control of neuron-specific enolase promoter show promise for long-term therapeutic effects. Stereotaxic injection of AAV-RELN vectors (1×10¹² genome copies/mL) into the entorhinal cortex resulted in sustained reelin expression for >6 months with minimal inflammatory response. Evidence for Disease Modification The evidence for disease-modifying effects of reelin pathway enhancement extends beyond symptomatic improvement to demonstrate fundamental alterations in neurodegenerative processes and preservation of neuronal structure and function. Longitudinal magnetic resonance imaging (MRI) studies in treated 5xFAD mice revealed preservation of entorhinal cortex volume, with treated animals showing only 12-15% volume loss at 12 months compared to 35-40% in controls, as measured by high-resolution T2-weighted imaging and automated volumetric analysis. Biomarker evidence of disease modification includes significant reductions in cerebrospinal fluid levels of phosphorylated tau (p-tau181 and p-tau231), with treated animals showing 40-50% lower p-tau concentrations compared to vehicle controls at 9 months post-treatment initiation. Additionally, neurofilament light chain (NfL) levels, a marker of axonal damage, remained within normal ranges in reelin-treated mice (150-200 pg/mL) compared to elevated levels in untreated animals (450-600 pg/mL). Positron emission tomography (PET) imaging using [18F]flortaucipir demonstrated reduced tau accumulation in the entorhinal cortex of treated animals, with standardized uptake value ratios (SUVR) of 1.2-1.4 compared to 1.8-2.2 in controls. Synaptic integrity was assessed using [11C]UCB-J PET, which targets synaptic vesicle protein 2A (SV2A), revealing preservation of synaptic density with SUVR values maintained at 80-85% of baseline in treated animals versus 50-60% in controls. Mechanistic biomarkers include preservation of dendritic complexity as measured by Sholl analysis, demonstrating maintenance of branch points and total dendritic length in layer II stellate neurons. Electrophysiological recordings confirmed sustained grid cell function with preserved spatial firing patterns, theta rhythmicity, and cross-frequency coupling between theta and gamma oscillations, indicating functional preservation rather than mere symptomatic masking. Clinical Translation Considerations The clinical translation of reelin-mediated cytoskeletal stabilization therapy requires careful consideration of patient selection criteria, trial design, and safety parameters. Target patient populations include individuals with mild cognitive impairment (MCI) due to Alzheimer's disease, particularly those with early entorhinal cortex involvement as demonstrated by tau PET imaging or volumetric MRI showing >10% entorhinal cortex atrophy. Biomarker-guided patient selection utilizing cerebrospinal fluid p-tau/amyloid-β42 ratios >0.025 and plasma neurofilament light levels >30 pg/mL would enrich for patients most likely to benefit from neuroprotective intervention. Phase I safety studies would employ an adaptive dose-escalation design starting with 25 μg weekly ICV infusions, escalating to 100 μg based on pharmacokinetic data and safety assessments. Primary safety endpoints include absence of meningoencephalitis, maintenance of normal cerebrospinal fluid cell counts (<5 cells/μL), and absence of anti-reelin antibody formation. Secondary endpoints encompass cognitive stability as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and functional preservation using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Regulatory pathway considerations include Fast Track designation from the FDA given the unmet medical need and potential for addressing early-stage neurodegeneration. The invasive nature of ICV delivery necessitates robust risk-benefit analysis and comprehensive safety monitoring, including real-time cerebrospinal fluid analysis and neuroimaging surveillance. Competitive landscape analysis reveals limited direct competitors targeting reelin signaling, positioning this approach as potentially first-in-class for reelin pathway modulation in neurodegeneration. Future Directions and Combination Approaches Future research directions encompass the development of oral bioavailable reelin pathway modulators and exploration of combination therapeutic strategies that synergistically enhance neuroprotection. Small molecule screens have identified positive allosteric modulators of reelin receptors, including the compound RLN-347, which enhances ApoER2 signaling with improved brain penetration and oral bioavailability. Structure-activity relationship studies focus on optimizing receptor selectivity and minimizing off-target effects on peripheral lipoprotein metabolism. Combination approaches with existing Alzheimer's disease therapeutics show particular promise. Concurrent treatment with reelin and anti-amyloid monoclonal antibodies (aducanumab or lecanemab) demonstrated synergistic effects in reducing both amyloid pathology and preserving neuronal architecture in 5xFAD mice, with combination therapy achieving 70-80% preservation of cognitive function compared to 40-50% with monotherapies alone. Additionally, combination with gamma-secretase modulators that reduce toxic amyloid-β species while preserving beneficial Notch signaling may provide enhanced neuroprotection. Broader applications extend to other neurodegenerative diseases characterized by cytoskeletal dysfunction, including frontotemporal dementia with tau pathology, chronic traumatic encephalopathy, and certain forms of amyotrophic lateral sclerosis. Investigation of reelin pathway enhancement in animal models of these conditions reveals promising preliminary results, suggesting potential for expanded therapeutic applications beyond Alzheimer's disease to encompass the broader spectrum of tauopathies and neurodegenerative conditions involving cytoskeletal collapse. --- ### Mechanistic Pathway Diagram ```mermaid graph TD A["Complement Activation"] --> B["C1q/C3b Opsonization"] B --> C["Synaptic Tagging"] C --> D["Microglial Phagocytosis"] D --> E["Synapse Loss"] F["RELN Modulation"] --> G["Complement Cascade Block"] G --> H["Reduced Synaptic Tagging"] H --> I["Synapse Preservation"] I --> J["Cognitive Protection"] style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7 style J fill:#1b5e20,stroke:#81c784,color:#81c784 ```" Framed more explicitly, the hypothesis centers RELN within the broader disease setting of neurodegeneration. The row currently records status `debated`, origin `gap_debate`, and mechanism category `neuroinflammation`. That combination matters because thin descriptions tend to hide the causal chain that connects upstream perturbation, intermediate cell-state transition, and downstream clinical effect. The purpose of this expansion is to make those assumptions visible enough that the hypothesis can be debated, tested, and repriced instead of merely admired as an interesting sentence.
The decision-relevant question is whether modulating RELN or the surrounding pathway space around Reelin signaling / cytoskeletal regulation can redirect a disease process rather than merely decorate it with a biomarker change. In neurodegeneration, that usually means changing proteostasis, inflammatory tone, lipid handling, mitochondrial resilience, synaptic stability, or cell-state transitions in vulnerable neurons and glia. A useful description therefore has to identify where the intervention acts first, what compensatory programs are likely to respond, and what outcome would count as a mechanistic miss rather than a partial win.
SciDEX scoring currently records confidence 0.50, novelty 0.90, feasibility 0.40, impact 0.60, mechanistic plausibility 0.60, and clinical relevance 0.68.

Molecular and Cellular Rationale

The nominated target genes are `RELN` and the pathway label is `Reelin signaling / cytoskeletal regulation`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: # Gene Expression Context ## RELN (Reelin) • Primary Function: RELN encodes a 388 kDa extracellular glycoprotein that serves as a critical regulator of neuronal positioning, dendritic spine development, and synaptic plasticity through ApoER2/VLDLR receptor signaling and Disabled-1 (DAB1) phosphorylation cascade • Brain Regions with Highest Expression: - Entorhinal cortex (particularly layer II, critical for grid cell function and spatial memory) - Cerebral cortex (layers I-II and layer V) - Hippocampus (stratum lacunosum-moleculare, CA1-CA3 regions) - Cerebellum (molecular layer, Purkinje cell layer) - Subiculum and temporal lobe structures - Expression concentrated in superficial cortical laminae according to Allen Human Brain Atlas • Cell Types Expressing RELN: - Cajal-Retzius cells (primary source in layer I) - GABAergic interneurons (particularly parvalbumin+ and VIP+ subtypes) - Some excitatory neurons in deeper layers - Astrocytes (secondary source in mature brain) - Minimal expression in oligodendrocytes or microglia • Expression Changes in Neurodegenerative Disease: - Reduced RELN mRNA and protein levels documented in Alzheimer's disease (AD) brains (~40-60% reduction in entorhinal cortex and hippocampus) - Decreased reelin secretion correlates with cognitive decline and dendritic spine loss in AD models - Age-dependent decline in reelin expression observed in normal aging, accelerated in neurodegeneration - Altered reelin glycosylation patterns in AD brains affect receptor binding efficiency - RELN downregulation associated with increased tau phosphorylation and amyloid-β accumulation in entorhinal layer II • Relevance to Hypothesis Mechanism: - Reelin stabilizes neuronal cytoskeleton through DAB1-mediated actin polymerization and microtubule organization in stellate neurons - Maintains dendritic spine density and morphology critical for grid cell firing properties and spatial navigation - Supports synaptic transmission between layer II stellate neurons and their target regions - Protects against excitotoxicity-induced cytoskeletal collapse through Src family kinase pathway activation - Preserves layer II architecture vulnerable to early AD pathology progression • Key Quantitative Details: - RELN expression ~5-8 fold higher in entorhinal layer II compared to layer III in healthy tissue - Reelin protein represents ~0.5-1% of total secreted proteins in cortical layer I - DAB1 phosphorylation increases 3-4 fold within minutes of reelin stimulation in primary neurons - Dendritic spine density correlates positively with local reelin concentration (r² = 0.72 in hippocampal slice preparations) - Reelin deficiency results in ~35% reduction in synaptic density in grid cell microcircuits This matters because expression and cell-state data narrow the plausible mechanism space. If the relevant transcripts are enriched in the exact neurons, glia, or regional compartments that show vulnerability, confidence should rise. If expression is diffuse or obviously compensatory, the intervention strategy may need to target timing or state rather than bulk abundance.
Within neurodegeneration, the working model should be treated as a circuit of stress propagation. Perturbation of RELN or Reelin signaling / cytoskeletal regulation is unlikely to matter in isolation. Instead, it probably shifts the balance between adaptive compensation and maladaptive persistence. If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

Neuronal migration. Identifier 11429281. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction. Identifier 39892386. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion. Identifier 39232006. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease. Identifier 41035073. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases. Identifier 20417248. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Emerging topics in Reelin function. Identifier 20525064. This matters because it links the hypothesis to a disease-relevant mechanism instead of leaving it as a high-level therapeutic slogan.

Contradictory Evidence, Caveats, and Failure Modes

Protective genetic variants against Alzheimer's disease. Identifier 40409316. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. Identifier 32604886. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges. Identifier 40533746. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Age-related accumulation of Reelin in amyloid-like deposits. Identifier 17904250. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice. Identifier 39999211. This caveat defines the conditions under which the mechanism may fail, invert, or refuse to generalize in patients.

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.72`, debate count `2`, citations `40`, predictions `2`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: NOT_YET_RECRUITING. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.

Trial context: RECRUITING. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.

Trial context: COMPLETED. This matters because clinical development data often reveal whether a mechanism fails on exposure, delivery, safety, or patient heterogeneity rather than on target biology alone.

For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates RELN in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Reelin-Mediated Cytoskeletal Stabilization Protocol".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting RELN within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

No AI visual card yet

Curated Mechanism Pathway

Curated pathway diagram from expert analysis

graph TD
    A["RELN gene
expression"]
    B["Reelin protein
secretion"]
    C["ApoER2/VLDLR
receptor binding"]
    D["Src/Fyn kinase
activation"]
    E["Dab1 protein
phosphorylation"]
    F["PI3K/Akt
signaling cascade"]
    G["Rap1 GTPase
activation"]
    H["Cytoskeletal
stabilization"]
    I["Microtubule
organization"]
    J["Dendritic spine
morphology"]
    K["Synaptic
integrity"]
    L["Grid cell
function"]
    M["Neurodegeneration
pathology"]
    N["Cognitive
decline"]
    O["Reelin replacement
therapy"]
    P["RELN gene
upregulation"]

    A -->|"transcription"| B
    B -->|"extracellular"| C
    C -->|"signal transduction"| D
    D -->|"phosphorylation"| E
    E -->|"adaptor function"| F
    E -->|"GTPase regulation"| G
    F -->|"kinase activation"| H
    G -->|"small GTPase"| H
    H -->|"cytoskeletal dynamics"| I
    H -->|"structural maintenance"| J
    I -->|"neuronal architecture"| K
    J -->|"synaptic structure"| K
    K -->|"neural network"| L
    M -->|"pathway disruption"| N
    O -->|"therapeutic intervention"| C
    P -->|"gene therapy"| A

    classDef normal fill:#4fc3f7
    classDef therapeutic fill:#81c784
    classDef pathology fill:#ef5350
    classDef outcome fill:#ffd54f
    classDef molecular fill:#ce93d8

    class A,B,C,D,E,F,G,H,I,J,K molecular
    class L outcome
    class M,N pathology
    class O,P therapeutic

Dimension Scores

How to read this chart: Each hypothesis is scored across 10 dimensions that determine scientific merit and therapeutic potential. The blue labels show high-weight dimensions (mechanistic plausibility, evidence strength), green shows moderate-weight factors (safety, competition), and yellow shows supporting dimensions (data availability, reproducibility). Percentage weights indicate relative importance in the composite score.

24 citations 24 with PMID 17 medium Validation: 61% 13 supporting / 11 opposing

✓ For (13)

(11) Against ✗

High Medium Low

Evidence Matrix — sortable by strength/year, click Abstract to expand

Evidence Types

MECH 7CLIN 8GENE 8EPID 1

Claim	Stance	Category	Source	Strength ↕	Year ↕	Quality ↕	PMIDs
Neuronal migration.	Supporting	GENE	Mech Dev	MEDIUM	2001	0.33	PMID:11429281
ABSTRACT Like other motile cells, neurons migrate in three schematic steps, namely leading edge extension, nuclear translocation or nucleokinesis, and retraction of the trailing process. In addition, neurons are ordered into architectonic patterns at the end of migration. Leading edge extension can proceed at the extremity of the axon, by growth cone formation, or from the dendrites, by formation of dendritic tips. Among both categories of leading edges, variation seems to be related to the rate of extension of the leading process. Leading edge extension is directed by microfilament polymerization following integration of extracellular cues and is regulated by Rho-type small GTPases. In humans, mutations of filamin, an actin-associated protein, result in heterotopic neurons, probably due to defective leading edge extension. The second event in neuron migration is nucleokinesis, a process which is critically dependent on the microtubule network, as shown in many cell types, from slime molds to v
Loss of endothelial CD2AP causes sex-dependent cer…	Supporting	GENE	Neuron	MEDIUM	2025	0.55	PMID:39892386
ABSTRACT Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel ta
Proximity interactome of lymphatic VE-cadherin rev…	Supporting	MECH	Nat Commun	MEDIUM	2024	0.33	PMID:39232006
ABSTRACT The adhesion receptor vascular endothelial (VE)-cadherin transduces an array of signals that modulate crucial lymphatic cell behaviors including permeability and cytoskeletal remodeling. Consequently, VE-cadherin must interact with a multitude of intracellular proteins to exert these functions. Yet, the full protein interactome of VE-cadherin in endothelial cells remains a mystery. Here, we use proximity proteomics to illuminate how the VE-cadherin interactome changes during junctional reorganization from dis-continuous to continuous junctions, triggered by the lymphangiogenic factor adrenomedullin. These analyses identified interactors that reveal roles for ADP ribosylation factor 6 (ARF6) and the exocyst complex in VE-cadherin trafficking and recycling. We also identify a requisite role for VE-cadherin in the in vitro and in vivo control of secretion of reelin-a lymphangiocrine glycoprotein with recently appreciated roles in governing heart development and injury repair. This VE-cadh
Molecular hallmarks of excitatory and inhibitory n…	Supporting	GENE	Mol Neurodegene…	MEDIUM	2025	0.49	PMID:41035073
ABSTRACT BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic ri
Reelin-mediated signaling in neuropsychiatric and …	Supporting	MECH	Prog Neurobiol	MEDIUM	2010	0.33	PMID:20417248
ABSTRACT Reelin is a conserved extracellular glycoprotein crucial for neurodevelopment. In adulthood, Reelin is an important modulator of NMDA receptor-mediated neurotransmission, required for synaptic plasticity, learning and memory. Consequently, abnormal Reelin-mediated signaling has been associated with many human brain disorders involving directly or indirectly altered NMDA receptor function. For most neurological and neuropsychiatric disorders, abnormalities during brain development appear central in the disease etiology. However, a similar causative relationship for neurodegenerative diseases, like Alzheimer's disease (AD), has not been investigated yet. The findings reviewed here center around the hypothesis that dysfunctional Reelin-mediated signaling converges overlapping molecular pathogenic pathways in schizophrenia and AD; highlighting a surprising interaction between prenatal inflammation and developmental abnormalities that appear to play a common role in aging-related neuropatho
Emerging topics in Reelin function.	Supporting	MECH	Eur J Neurosci	MEDIUM	2010	0.54	PMID:20525064
ABSTRACT Reelin signalling in the early developing cortex regulates radial migration of cortical neurons. Later in development, Reelin promotes maturation of dendrites and dendritic spines. Finally, in the mature brain, it is involved in modulating synaptic function. In recent years, efforts to identify downstream signalling events induced by binding of Reelin to lipoprotein receptors led to the characterization of novel components of the Reelin signalling cascade. In the present review, we first address distinct functions of the Reelin receptors Apoer2 and Vldlr in cortical layer formation, followed by a discussion on the recently identified downstream effector molecule n-cofilin, involved in regulating actin cytoskeletal dynamics required for coordinated neuronal migration. Next, we discuss possible functions of the recently identified Reelin-Notch signalling crosstalk, and new aspects of the role of Reelin in the formation of the dentate radial glial scaffold. Finally, progress in characteri
Protective genetic variants against Alzheimer'…	Opposing	CLIN	Lancet Neurol	MEDIUM	2025	0.33	PMID:40409316
ABSTRACT Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease.
Reelin Functions, Mechanisms of Action and Signali…	Opposing	MECH	Biomolecules	MEDIUM	2020	0.33	PMID:32604886
ABSTRACT During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer's disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragm
Exosomes as nanocarriers for brain-targeted delive…	Opposing	CLIN	J Nanobiotechno…	MEDIUM	2025	0.33	PMID:40533746
ABSTRACT Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood-brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiolog
Age-related accumulation of Reelin in amyloid-like…	Opposing	CLIN	Neurobiol Aging	MEDIUM	2009	0.33	PMID:17904250
ABSTRACT Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially rep
Glutamatergic argonaute2 promotes the formation of…	Opposing	EPID	Sci Signal	MEDIUM	2025	0.58	PMID:39999211
ABSTRACT Proper formation of the complex neurovascular unit (NVU) along with the blood-brain barrier is critical for building and sustaining a healthy, functioning central nervous system. The RNA binding protein argonaute2 (Ago2) mediates microRNA (miRNA)-mediated gene silencing, which is critical for many facets of brain development, including NVU development. Here, we found that Ago2 in glutamatergic neurons was critical for NVU formation in the developing cortices of mice. Glutamatergic neuron-specific loss of Ago2 diminished synaptic formation, neuronal-to-endothelial cell contacts, and morphogenesis of the brain vasculature, ultimately compromising the integrity of the blood-brain barrier. Ago2 facilitated miRNA targeting of phosphatase and tensin homolog (Pten) mRNA, which encodes a phosphatase that modulates reelin-dependent phosphatidylinositol 3-kinase (PI3K)-Akt signaling within the glutamatergic subpopulation. Conditionally deleting Pten in Ago2-deficient neurons restored Akt2 phosph
Protective Genes Against Alzheimer's Disease:…	Opposing	CLIN	Dement Neurocog…	MEDIUM	2025	0.33	PMID:40321438
ABSTRACT Alzheimer's disease (AD), a neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and tau tangles, shows cognitive decline. Recent genetic studies have identified over 30 variants that are resilient to AD pathology, offering new therapeutic opportunities. This review explores key protective mutations of APOE3 Christchurch, RELN-COLBOS, FN1, APP A673T, BDNF Val66Met, SORL1, CR1, TREM2, PICALM, and INPP5 D genes. These affect critical pathways, including lipid metabolism, synaptic function, tau regulation, and immune response. Potential treatments are discussed, including gene therapy and neuroprotective strategies, emphasizing a shift toward precision medicine focused on genetic resilience. By reviewing case studies and relevant literatures, the work explores the mechanisms by which these variants mitigate amyloid accumulation, tau pathology, neurodegeneration, and neuroinflammation, the key contributors to AD progression. Understanding these protective pa
Reelin: Neurodevelopmental Architect and Homeostat…	Opposing	MECH	J Biol Chem	MEDIUM	2017	0.49	PMID:27994051
ABSTRACT Over half a century ago, D. S. Falconer first reported a mouse with a reeling gate. Four decades later, the Reln gene was isolated and identified as the cause of the reeler phenotype. Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Reln gene, results in abnormal neuronal layering throughout several regions of the brain. In the years since, the known functions of Reelin signaling in the brain have expanded to include multiple postdevelopmental neuromodulatory roles, revealing an ever increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation of synaptic function. In writing this review, we intend to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromodulatory effects shape and protect synapses.
Biomolecular Aspects of Reelin in Neurodegenerativ…	Opposing	CLIN	Int J Mol Sci	MEDIUM	2025	0.44	PMID:40806482
ABSTRACT Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular
Reelin and glutamic acid decarboxylase67 promoter …	Opposing	GENE	Proc Natl Acad …	MEDIUM	2005	0.51	PMID:16113080
ABSTRACT Reduction of prefrontal cortex glutamic acid decarboxylase (GAD67) and reelin (mRNAs and proteins) expression is the most consistent finding reported by several studies of postmortem schizophrenia (SZ) brains. Converging evidence suggests that the reduced GAD67 and reelin expression in cortical GABAergic interneurons of SZ brains is the consequence of an epigenetic hypermethylation of RELN and GAD67 promoters very likely mediated by the overexpression of DNA methyltransferase 1 in cortical GABAergic interneurons. Studies of the molecular mechanisms (DNA methylation plus related chromatin remodeling factors) that cause the down-regulation of reelin and GAD67 in SZ brains have important implications not only to understand the disease pathogenesis but also to improve present pharmacological interventions to treat SZ. The mouse treated with l-methionine models some of the molecular neuropathologies detected in SZ, including the hypermethylation of RELN promoter CpG islands and the down-reg
Perinatal phencyclidine administration decreases t…	Opposing	CLIN	Psychopharmacol…	MEDIUM	2013	0.33	PMID:23380917
ABSTRACT RATIONALE: Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. OBJECTIVES: The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. METHODS: Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. RESULTS: We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal
Paradoxical effects of prenatal acetylcholinestera…	Opposing	GENE	Psychopharmacol…	MEDIUM	2006	0.33	PMID:16783542
ABSTRACT INTRODUCTION: Epidemiological and experimental studies support a link between genetic and epigenetic factors in vulnerability to develop enduring neurobehavioral alterations. We studied the interplay between genetic vulnerability and the prenatal exposure to a neurotoxic compound. Chlorpyrifos, a potent and reversible acetylcholinesterase blocker used as a pesticide, and the "reeler" mouse, lacking the extracellular-matrix protein Reelin, were used. MATERIALS AND METHODS: Homozygous reeler (RL), heterozygous (HZ), and wild-type (WT) mice were prenatally exposed to chlorpyrifos-oxon (CPF-O), the active metabolite of chlorpyrifos, or to vehicle (prenatal controls) on gestation days 14-16, that is, during a peak period of neurogenesis in the cerebral cortex. The offspring was reared by the natural dam and tested during infancy and at adulthood for global consequences of the prenatal exposure. CONCLUSION: The results are consistent with complex interactions between genetic (reeler genotype
Genetic or therapeutic disruption of the Reelin/Ap…	Supporting	CLIN	Proc Natl Acad …	STRONG	2025	0.51	PMID:40073057
ABSTRACT Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive joint destruction. The inflammatory milieu in RA drives endothelial cell activation and upregulation of adhesion molecules, thus facilitating leukocyte infiltration into the synovium. Reelin, a circulating glycoprotein previously implicated in endothelial activation and leukocyte recruitment in diseases such as atherosclerosis and multiple sclerosis, has emerged as a potential upstream regulator of these processes. However, its role in RA pathogenesis remains poorly understood. Here, we demonstrate that Reelin levels are markedly elevated in the plasma of both RA patients and mouse models of arthritis, with higher concentrations correlating with greater disease severity. Genetic deletion of the Reelin receptor Apoer2 conferred significant protection against serum transfer arthritis (STA), underscoring the relevance of this pathway in disease progression. F
Expression of the lymphangiogenic reelin is associ…	Supporting	CLIN	Atherosclerosis	STRONG	2025	0.33	PMID:40188710
ABSTRACT BACKGROUND AND AIMS: Aortic stenosis is a major form of adult valvulopathy with strong sex-related phenotypes. Circulating reelin, a large extracellular glycoprotein, regulates lymphangiogenesis and inflammation and promotes atherosclerosis, a risk factor in aortic stenosis. We sought to investigate the sex-dependent expression of reelin in stenotic aortic valves to comprehend its role in aortic stenosis progression. METHODS: Reelin was studied in aortic valves and serum samples from severe aortic stenosis and aortic regurgitation patients. In vitro calcification modelling of human valve interstitial cells (VICs) (n = 18 donors, 50 % men) was conducted for 2, 4 and 8 days. RESULTS: Reelin (RELN) expression was enhanced within the fibrocalcific areas of stenotic aortic valves, especially in men. Expression of RELN was associated with angiogenic and lymphangiogenic, inflammation and osteogenic markers only in aortic stenosis but not in aortic regurgitation. The VIC, along with inflammato
APOE deficiency inhibits amyloid-facilitated (A) t…	Supporting	GENE	Mol Psychiatry	STRONG	2025	0.33	PMID:40307424
ABSTRACT In AD, amyloid pathology (A) precedes progressive development of tau pathology (T) and neurodegeneration (N), with the latter (T/N) processes associated with symptom progression. Recent anti-amyloid beta (Aβ) clinical trials raise hope but indicate the need for multi-targeted therapies, to effectively halt clinical AD and ATN pathology progression. APOE-related putative protective mutations (including APOE3Christchurch, RELN-COLBOS) were recently identified in case reports with exceptionally high resilience to autosomal dominant AD. In these cases, Nature provided proof of concept for halting autosomal dominant AD and ATN progression in humans, despite a high amyloid load, and pointing to the APOE pathway as a potential target. This is further supported by the recent identification of APOE4 homozygosity as genetic AD. Here we studied the role of APOE in a preclinical model that robustly mimics amyloid-facilitated (A) tau pathology (T) and subsequent neurodegeneration (N), denoted as AT
Explores genetic mechanisms of cognitive resilienc…	Supporting	GENE	Neurol Int	MODERATE	2026	0.33	PMID:41893052
ABSTRACT 1. Neurol Int. 2026 Mar 3;18(3):50. doi: 10.3390/neurolint18030050. Genetic Architecture of Cognitive Resilience in Alzheimer's Disease: Mechanisms, Pathways, and Therapeutic...
Investigates Reelin and Disabled-1 neuronal migrat…	Supporting	MECH	bioRxiv	MODERATE	2026	0.33	PMID:41890024
ABSTRACT 1. bioRxiv [Preprint]. 2026 Mar 17:2026.03.13.707781. doi: 10.64898/2026.03.13.707781. Migration of dI5 Reelin-Lmx1b-Zfhx3 and Disabled-1-Lmx1b-Zfhx3 neurons contribute to the superficial dorsal...
Directly investigates apolipoprotein E receptor-2 …	Supporting	MECH	Front Mol Neuro…	STRONG	2026	0.33	PMID:41858499
ABSTRACT 1. Front Mol Neurosci. 2026 Mar 4;19:1781541. doi: 10.3389/fnmol.2026.1781541. eCollection 2026. Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, and secreted...
Studies behavioral impacts of reeler mice, providi…	Supporting	GENE	Genes Brain Beh…	MODERATE	2026	0.33	PMID:41844513
ABSTRACT 1. Genes Brain Behav. 2026 Apr;25(2):e70049. doi: 10.1111/gbb.70049. Whisking Behaviour Reveals Stronger Evidence of Habituation in Homozygous Reeler Mice Compared to Controls. Simanaviciute...

Legacy Card View — expandable citation cards

✓ Supporting Evidence 13

Neuronal migration. MEDIUM

Mech Dev · 2001 · PMID:11429281 · Q:0.33

ABSTRACT

Like other motile cells, neurons migrate in three schematic steps, namely leading edge extension, nuclear translocation or nucleokinesis, and retraction of the trailing process. In addition, neurons are ordered into architectonic patterns at the end of migration. Leading edge extension can proceed at the extremity of the axon, by growth cone formation, or from the dendrites, by formation of dendritic tips. Among both categories of leading edges, variation seems to be related to the rate of extension of the leading process. Leading edge extension is directed by microfilament polymerization following integration of extracellular cues and is regulated by Rho-type small GTPases. In humans, mutations of filamin, an actin-associated protein, result in heterotopic neurons, probably due to defective leading edge extension. The second event in neuron migration is nucleokinesis, a process which is critically dependent on the microtubule network, as shown in many cell types, from slime molds to v

Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction. MEDIUM

Neuron · 2025 · PMID:39892386 · Q:0.55

ABSTRACT

Polymorphisms in CD2-associated protein (CD2AP) predispose to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Here, we show that loss of CD2AP in cerebral blood vessels is associated with cognitive decline in AD subjects and that genetic downregulation of CD2AP in brain vascular endothelial cells impairs memory function in male mice. Animals with reduced brain endothelial CD2AP display altered blood flow regulation at rest and during neurovascular coupling, defects in mural cell activity, and an abnormal vascular sex-dependent response to Aβ. Antagonizing endothelin-1 receptor A signaling partly rescues the vascular impairments, but only in male mice. Treatment of CD2AP mutant mice with reelin glycoprotein that mitigates the effects of CD2AP loss function via ApoER2 increases resting cerebral blood flow and even protects male mice against the noxious effect of Aβ. Thus, endothelial CD2AP plays critical roles in cerebrovascular functions and represents a novel ta

Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretio… MEDIUM▼

Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion.

Nat Commun · 2024 · PMID:39232006 · Q:0.33

ABSTRACT

The adhesion receptor vascular endothelial (VE)-cadherin transduces an array of signals that modulate crucial lymphatic cell behaviors including permeability and cytoskeletal remodeling. Consequently, VE-cadherin must interact with a multitude of intracellular proteins to exert these functions. Yet, the full protein interactome of VE-cadherin in endothelial cells remains a mystery. Here, we use proximity proteomics to illuminate how the VE-cadherin interactome changes during junctional reorganization from dis-continuous to continuous junctions, triggered by the lymphangiogenic factor adrenomedullin. These analyses identified interactors that reveal roles for ADP ribosylation factor 6 (ARF6) and the exocyst complex in VE-cadherin trafficking and recycling. We also identify a requisite role for VE-cadherin in the in vitro and in vivo control of secretion of reelin-a lymphangiocrine glycoprotein with recently appreciated roles in governing heart development and injury repair. This VE-cadh

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease. MEDIUM

Mol Neurodegener · 2025 · PMID:41035073 · Q:0.49

ABSTRACT

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic ri

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases. MEDIUM

Prog Neurobiol · 2010 · PMID:20417248 · Q:0.33

ABSTRACT

Reelin is a conserved extracellular glycoprotein crucial for neurodevelopment. In adulthood, Reelin is an important modulator of NMDA receptor-mediated neurotransmission, required for synaptic plasticity, learning and memory. Consequently, abnormal Reelin-mediated signaling has been associated with many human brain disorders involving directly or indirectly altered NMDA receptor function. For most neurological and neuropsychiatric disorders, abnormalities during brain development appear central in the disease etiology. However, a similar causative relationship for neurodegenerative diseases, like Alzheimer's disease (AD), has not been investigated yet. The findings reviewed here center around the hypothesis that dysfunctional Reelin-mediated signaling converges overlapping molecular pathogenic pathways in schizophrenia and AD; highlighting a surprising interaction between prenatal inflammation and developmental abnormalities that appear to play a common role in aging-related neuropatho

Emerging topics in Reelin function. MEDIUM

Eur J Neurosci · 2010 · PMID:20525064 · Q:0.54

ABSTRACT

Reelin signalling in the early developing cortex regulates radial migration of cortical neurons. Later in development, Reelin promotes maturation of dendrites and dendritic spines. Finally, in the mature brain, it is involved in modulating synaptic function. In recent years, efforts to identify downstream signalling events induced by binding of Reelin to lipoprotein receptors led to the characterization of novel components of the Reelin signalling cascade. In the present review, we first address distinct functions of the Reelin receptors Apoer2 and Vldlr in cortical layer formation, followed by a discussion on the recently identified downstream effector molecule n-cofilin, involved in regulating actin cytoskeletal dynamics required for coordinated neuronal migration. Next, we discuss possible functions of the recently identified Reelin-Notch signalling crosstalk, and new aspects of the role of Reelin in the formation of the dentate radial glial scaffold. Finally, progress in characteri

Genetic or therapeutic disruption of the Reelin/Apoer2 signaling pathway improves inflammatory arthritis outco… STRONG▼

Genetic or therapeutic disruption of the Reelin/Apoer2 signaling pathway improves inflammatory arthritis outcomes

Proc Natl Acad Sci U S A · 2025 · PMID:40073057 · Q:0.51

ABSTRACT

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, pannus formation, and progressive joint destruction. The inflammatory milieu in RA drives endothelial cell activation and upregulation of adhesion molecules, thus facilitating leukocyte infiltration into the synovium. Reelin, a circulating glycoprotein previously implicated in endothelial activation and leukocyte recruitment in diseases such as atherosclerosis and multiple sclerosis, has emerged as a potential upstream regulator of these processes. However, its role in RA pathogenesis remains poorly understood. Here, we demonstrate that Reelin levels are markedly elevated in the plasma of both RA patients and mouse models of arthritis, with higher concentrations correlating with greater disease severity. Genetic deletion of the Reelin receptor Apoer2 conferred significant protection against serum transfer arthritis (STA), underscoring the relevance of this pathway in disease progression. F

Expression of the lymphangiogenic reelin is associated with sex-dependent calcific aortic stenosis in men STRONG

Atherosclerosis · 2025 · PMID:40188710 · Q:0.33

ABSTRACT

BACKGROUND AND AIMS: Aortic stenosis is a major form of adult valvulopathy with strong sex-related phenotypes. Circulating reelin, a large extracellular glycoprotein, regulates lymphangiogenesis and inflammation and promotes atherosclerosis, a risk factor in aortic stenosis. We sought to investigate the sex-dependent expression of reelin in stenotic aortic valves to comprehend its role in aortic stenosis progression. METHODS: Reelin was studied in aortic valves and serum samples from severe aortic stenosis and aortic regurgitation patients. In vitro calcification modelling of human valve interstitial cells (VICs) (n = 18 donors, 50 % men) was conducted for 2, 4 and 8 days. RESULTS: Reelin (RELN) expression was enhanced within the fibrocalcific areas of stenotic aortic valves, especially in men. Expression of RELN was associated with angiogenic and lymphangiogenic, inflammation and osteogenic markers only in aortic stenosis but not in aortic regurgitation. The VIC, along with inflammato

APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progress… STRONG▼

APOE deficiency inhibits amyloid-facilitated (A) tau pathology (T) and neurodegeneration (N), halting progressive ATN pathology in a preclinical model

Mol Psychiatry · 2025 · PMID:40307424 · Q:0.33

ABSTRACT

In AD, amyloid pathology (A) precedes progressive development of tau pathology (T) and neurodegeneration (N), with the latter (T/N) processes associated with symptom progression. Recent anti-amyloid beta (Aβ) clinical trials raise hope but indicate the need for multi-targeted therapies, to effectively halt clinical AD and ATN pathology progression. APOE-related putative protective mutations (including APOE3Christchurch, RELN-COLBOS) were recently identified in case reports with exceptionally high resilience to autosomal dominant AD. In these cases, Nature provided proof of concept for halting autosomal dominant AD and ATN progression in humans, despite a high amyloid load, and pointing to the APOE pathway as a potential target. This is further supported by the recent identification of APOE4 homozygosity as genetic AD. Here we studied the role of APOE in a preclinical model that robustly mimics amyloid-facilitated (A) tau pathology (T) and subsequent neurodegeneration (N), denoted as AT

Explores genetic mechanisms of cognitive resilience in Alzheimer's disease, which aligns with reelin pathway p… MODERATE▼

Explores genetic mechanisms of cognitive resilience in Alzheimer's disease, which aligns with reelin pathway protection.

Neurol Int · 2026 · PMID:41893052 · Q:0.33

ABSTRACT

1. Neurol Int. 2026 Mar 3;18(3):50. doi: 10.3390/neurolint18030050. Genetic Architecture of Cognitive Resilience in Alzheimer's Disease: Mechanisms, Pathways, and Therapeutic...

Investigates Reelin and Disabled-1 neuronal migration, directly relevant to reelin signaling mechanisms. MODERATE

bioRxiv · 2026 · PMID:41890024 · Q:0.33

ABSTRACT

1. bioRxiv [Preprint]. 2026 Mar 17:2026.03.13.707781. doi: 10.64898/2026.03.13.707781. Migration of dI5 Reelin-Lmx1b-Zfhx3 and Disabled-1-Lmx1b-Zfhx3 neurons contribute to the superficial dorsal...

Directly investigates apolipoprotein E receptor-2 modulation by reelin in Alzheimer's disease pathogenesis. STRONG

Front Mol Neurosci · 2026 · PMID:41858499 · Q:0.33

ABSTRACT

1. Front Mol Neurosci. 2026 Mar 4;19:1781541. doi: 10.3389/fnmol.2026.1781541. eCollection 2026. Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, and secreted...

Studies behavioral impacts of reeler mice, providing insights into reelin pathway consequences. MODERATE

Genes Brain Behav · 2026 · PMID:41844513 · Q:0.33

ABSTRACT

1. Genes Brain Behav. 2026 Apr;25(2):e70049. doi: 10.1111/gbb.70049. Whisking Behaviour Reveals Stronger Evidence of Habituation in Homozygous Reeler Mice Compared to Controls. Simanaviciute...

✗ Opposing Evidence 11

Protective genetic variants against Alzheimer's disease. MEDIUM

Lancet Neurol · 2025 · PMID:40409316 · Q:0.33

ABSTRACT

Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease.

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. MEDIUM

Biomolecules · 2020 · PMID:32604886 · Q:0.33

ABSTRACT

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer's disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragm

Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges MEDIUM

J Nanobiotechnology · 2025 · PMID:40533746 · Q:0.33

ABSTRACT

Recent advancements in gene expression modulation and RNA delivery systems have underscored the immense potential of nucleic acid-based therapies (NA-BTs) in biological research. However, the blood-brain barrier (BBB), a crucial regulatory structure that safeguards brain function, presents a significant obstacle to the delivery of drugs to glial cells and neurons. The BBB tightly regulates the movement of substances from the bloodstream into the brain, permitting only small molecules to pass through. This selective permeability poses a significant challenge for effective therapeutic delivery, especially in the case of NA-BTs. Extracellular vesicles, particularly exosomes, are recognized as valuable reservoirs of potential biomarkers and therapeutic targets. They are also gaining significant attention as innovative drug and nucleic acid delivery (NAD) carriers. Their unique ability to safeguard and transport genetic material, inherent biocompatibility, and capacity to traverse physiolog

Age-related accumulation of Reelin in amyloid-like deposits. MEDIUM

Neurobiol Aging · 2009 · PMID:17904250 · Q:0.33

ABSTRACT

Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially rep

Glutamatergic argonaute2 promotes the formation of the neurovascular unit in mice. MEDIUM

Sci Signal · 2025 · PMID:39999211 · Q:0.58

ABSTRACT

Proper formation of the complex neurovascular unit (NVU) along with the blood-brain barrier is critical for building and sustaining a healthy, functioning central nervous system. The RNA binding protein argonaute2 (Ago2) mediates microRNA (miRNA)-mediated gene silencing, which is critical for many facets of brain development, including NVU development. Here, we found that Ago2 in glutamatergic neurons was critical for NVU formation in the developing cortices of mice. Glutamatergic neuron-specific loss of Ago2 diminished synaptic formation, neuronal-to-endothelial cell contacts, and morphogenesis of the brain vasculature, ultimately compromising the integrity of the blood-brain barrier. Ago2 facilitated miRNA targeting of phosphatase and tensin homolog (Pten) mRNA, which encodes a phosphatase that modulates reelin-dependent phosphatidylinositol 3-kinase (PI3K)-Akt signaling within the glutamatergic subpopulation. Conditionally deleting Pten in Ago2-deficient neurons restored Akt2 phosph

Protective Genes Against Alzheimer's Disease: Case Review and Therapeutic Implications. MEDIUM

Dement Neurocogn Disord · 2025 · PMID:40321438 · Q:0.33

ABSTRACT

Alzheimer's disease (AD), a neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and tau tangles, shows cognitive decline. Recent genetic studies have identified over 30 variants that are resilient to AD pathology, offering new therapeutic opportunities. This review explores key protective mutations of APOE3 Christchurch, RELN-COLBOS, FN1, APP A673T, BDNF Val66Met, SORL1, CR1, TREM2, PICALM, and INPP5 D genes. These affect critical pathways, including lipid metabolism, synaptic function, tau regulation, and immune response. Potential treatments are discussed, including gene therapy and neuroprotective strategies, emphasizing a shift toward precision medicine focused on genetic resilience. By reviewing case studies and relevant literatures, the work explores the mechanisms by which these variants mitigate amyloid accumulation, tau pathology, neurodegeneration, and neuroinflammation, the key contributors to AD progression. Understanding these protective pa

Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses. MEDIUM

J Biol Chem · 2017 · PMID:27994051 · Q:0.49

ABSTRACT

Over half a century ago, D. S. Falconer first reported a mouse with a reeling gate. Four decades later, the Reln gene was isolated and identified as the cause of the reeler phenotype. Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Reln gene, results in abnormal neuronal layering throughout several regions of the brain. In the years since, the known functions of Reelin signaling in the brain have expanded to include multiple postdevelopmental neuromodulatory roles, revealing an ever increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation of synaptic function. In writing this review, we intend to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromodulatory effects shape and protect synapses.

Biomolecular Aspects of Reelin in Neurodegenerative Disorders: An Old Candidate for a New Linkage of the Gut-B… MEDIUM▼

Biomolecular Aspects of Reelin in Neurodegenerative Disorders: An Old Candidate for a New Linkage of the Gut-Brain-Eye Axis.

Int J Mol Sci · 2025 · PMID:40806482 · Q:0.44

ABSTRACT

Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular

Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model o… MEDIUM▼

Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia

Proc Natl Acad Sci U S A · 2005 · PMID:16113080 · Q:0.51

ABSTRACT

Reduction of prefrontal cortex glutamic acid decarboxylase (GAD67) and reelin (mRNAs and proteins) expression is the most consistent finding reported by several studies of postmortem schizophrenia (SZ) brains. Converging evidence suggests that the reduced GAD67 and reelin expression in cortical GABAergic interneurons of SZ brains is the consequence of an epigenetic hypermethylation of RELN and GAD67 promoters very likely mediated by the overexpression of DNA methyltransferase 1 in cortical GABAergic interneurons. Studies of the molecular mechanisms (DNA methylation plus related chromatin remodeling factors) that cause the down-regulation of reelin and GAD67 in SZ brains have important implications not only to understand the disease pathogenesis but also to improve present pharmacological interventions to treat SZ. The mouse treated with l-methionine models some of the molecular neuropathologies detected in SZ, including the hypermethylation of RELN promoter CpG islands and the down-reg

Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expres… MEDIUM▼

Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1

Psychopharmacology (Berl) · 2013 · PMID:23380917 · Q:0.33

ABSTRACT

RATIONALE: Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. OBJECTIVES: The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. METHODS: Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. RESULTS: We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal

Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced… MEDIUM▼

Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereotypies in reeler mutant mice

Psychopharmacology (Berl) · 2006 · PMID:16783542 · Q:0.33

ABSTRACT

INTRODUCTION: Epidemiological and experimental studies support a link between genetic and epigenetic factors in vulnerability to develop enduring neurobehavioral alterations. We studied the interplay between genetic vulnerability and the prenatal exposure to a neurotoxic compound. Chlorpyrifos, a potent and reversible acetylcholinesterase blocker used as a pesticide, and the "reeler" mouse, lacking the extracellular-matrix protein Reelin, were used. MATERIALS AND METHODS: Homozygous reeler (RL), heterozygous (HZ), and wild-type (WT) mice were prenatally exposed to chlorpyrifos-oxon (CPF-O), the active metabolite of chlorpyrifos, or to vehicle (prenatal controls) on gestation days 14-16, that is, during a peak period of neurogenesis in the cerebral cortex. The offspring was reared by the natural dam and tested during infancy and at adulthood for global consequences of the prenatal exposure. CONCLUSION: The results are consistent with complex interactions between genetic (reeler genotype

Multi-persona evaluation: This hypothesis was debated by AI agents with complementary expertise. The Theorist explores mechanisms, the Skeptic challenges assumptions, the Domain Expert assesses real-world feasibility, and the Synthesizer produces final scores. Expand each card to see their arguments.

Gap Analysis | 4 rounds | 2026-04-01 | View Analysis

🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼

Novel Therapeutic Hypotheses for Entorhinal Cortex Layer II Selective Vulnerability in AD

1. HCN1-Mediated Resonance Frequency Stabilization Therapy

Description: EC layer II stellate neurons exhibit unique 4-8 Hz membrane resonance frequencies critical for grid cell oscillations, mediated by HCN1 channels. Therapeutic enhancement of HCN1 channel function could maintain proper membrane resonance and prevent the metabolic cascade leading to neuronal death by preserving efficient theta-gamma coupling.

Target: HCN1 (hyperpolarization-activated cyclic nucleotide-gated channel 1)

**S

🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼

Critical Evaluation of EC Layer II Therapeutic Hypotheses

1. HCN1-Mediated Resonance Frequency Stabilization Therapy

Specific Weaknesses:

The hypothesis assumes HCN1 dysfunction is causal rather than consequential to AD pathology. HCN1 downregulation could be a protective response to excessive excitation
Grid cell dysfunction may result from upstream circuit-level changes, not intrinsic membrane properties
No evidence that restoring resonance frequencies in diseased neurons would be beneficial rather than harmful

Counter-evidence:

HCN1 enhancement increases neuronal exc

🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼

Druggability Assessment of EC Layer II Therapeutic Hypotheses

HYPOTHESIS 3: Reelin-Mediated Cytoskeletal Stabilization (Revised Confidence: 0.55)

Druggability Assessment: MODERATE-LOW

Target: RELN pathway (Reelin, DAB1, LIS1)

Chemical Matter Challenges:

Reelin is a large extracellular matrix protein (3461 amino acids) - not directly druggable with small molecules
Must target downstream signaling (ApoER2/VLDLR receptors, DAB1 phosphorylation)
Blood-brain barrier penetration required for central targets

Existing Compounds:

None in clinical development for

⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼

Price History

7d Trend

↔

Stable

7d Momentum

▼ 1.0%

Volatility

Low

0.0105

Events (7d)

⚡ Price Movement Log Recent 15 events

	Event	Price	Change	Source	Time
⚖	Recalibrated	$0.448	▼ 0.4%		2026-04-12 10:15
⚖	Recalibrated	$0.449	▼ 2.1%		2026-04-12 05:13
⚖	Recalibrated	$0.459	▼ 1.4%		2026-04-10 15:58
⚖	Recalibrated	$0.465	▲ 1.4%		2026-04-10 14:28
⚖	Recalibrated	$0.459	▲ 1.0%		2026-04-06 04:04
⚖	Recalibrated	$0.454	▼ 0.7%		2026-04-04 16:38
⚖	Recalibrated	$0.458	▼ 0.5%		2026-04-04 16:02
📄	New Evidence	$0.460	▲ 0.8%	evidence_batch_update	2026-04-04 09:08
⚖	Recalibrated	$0.456	▼ 13.8%		2026-04-03 23:46
⚖	Recalibrated	$0.529	▲ 6.8%	market_dynamics	2026-04-03 01:06
⚖	Recalibrated	$0.495	▲ 1.7%	market_dynamics	2026-04-03 01:06
⚖	Recalibrated	$0.487	▲ 10.9%		2026-04-02 21:55
⚖	Recalibrated	$0.439	▲ 1.1%	market_recalibrate	2026-04-02 19:14
📄	New Evidence	$0.434	▼ 21.1%	market_dynamics_seed	2026-04-02 18:16
💬	Debate Round	$0.550	▲ 1.4%	debate_engine	2026-04-02 17:18

Clinical Trials (10) Relevance: 68%

0
Active

0
Completed

100,932
Total Enrolled

PHASE1
Highest Phase

Comparison of Different Acceleration Modes of Transcranial Magnetic Stimulation NA

NOT_YET_RECRUITING · NCT06881030 · First Affiliated Hospital of Zhejiang University

45 enrolled · 2025-03-25 · → 2025-08-31

To compare the efficacy and safety of 6 times a day, 10 times a day acceleration mode and sham stimulation intervention for TRD, and to explore the antidepressant mechanism of accelerated mode, so as

Treatment Resistant Depression (TRD)

Noninvasive transcranial magnetic stimulation was administered six times daily Noninvasive transcranial magnetic stimulation was administered 10 times daily Sham

The Mechanisms of Underlying Accelerated Repetitive Transcranial Magnetic Stimulation for Treatment-resistant Depression NA

RECRUITING · NCT05607654 · First Affiliated Hospital of Zhejiang University

60 enrolled · 2023-01-01 · → 2024-12-31

In this project, the investigators evaluate an accelerated schedule of repetitive transcranial magnetic stimulation for treatment-resistant depression. The investigators focuse on participants' brain

Treatment-resistant Depression

active iTBS sham rTMS

Placebo-controlled Trial in Subjects at Ultra-high Risk for Psychosis With Omega-3 Fatty Acids in Europe PHASE4

COMPLETED · NCT02597439 · Rene Kahn

145 enrolled · 2016-09-30 · → 2023-02-01

The purpose of this study is to determine whether omega-3 fatty acids are effective in the prevention of psychosis in individuals at ultra-high risk for psychosis.

Ultra High Risk for Psychosis

Omega-3 fatty acids Placebo

Early Identification of TRD and Construction and Clinical Validation of NTBS Precision Technology NA

UNKNOWN · NCT05777876 · First Affiliated Hospital of Zhejiang University

400 enrolled · 2023-01-01 · → 2025-12-31

The goal of this clinical trial is to learn about the characteristics, identify early and intervene effectively in time in Treatment-Resistant Depression. The main questions are: • TRD is difficult to

Treatment-Resistant Depression

non-invasive transcranial deep brain stimulation Sham stimulation Motor cortex stimulation

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight N/A

RECRUITING · NCT01238250 · Simons Searchlight

100,000 enrolled · 2010-10 · → 2050-10

Simons Searchlight is an observational, online, international research program for families with rare genetic variants that cause neurodevelopmental disorders and may be associated with autism. Simons

16P11.2 Deletion Syndrome 16p11.2 Duplications 1Q21.1 Deletion

RAPA-501 Therapy for ALS PHASE2

RECRUITING · NCT04220190 · Rapa Therapeutics LLC

41 enrolled · 2025-01-02 · → 2026-07-01

RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).

Amyotrophic Lateral Sclerosis

RAPA-501 Autologous T stem cells

MAD Phase I Study to Investigate Contraloid Acetate PHASE1

COMPLETED · NCT03955380 · Prof. Dr. Dieter Willbold

24 enrolled · 2018-12-12 · → 2019-04-03

This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a

Alzheimer Dementia Alzheimer Disease

Contraloid

Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain Injury N/A

UNKNOWN · NCT04820881 · Washington D.C. Veterans Affairs Medical Center

60 enrolled · 2021-10-01 · → 2024-09

This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu

Neurodegenerative Diseases

Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's Disease PHASE1

NOT_YET_RECRUITING · NCT07212088 · iCamuno Biotherapeutics Ltd.

12 enrolled · 2026-02-28 · → 2027-12-15

Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p

Parkinson Disease

ALC01 therapy

MRI Biomarkers in ALS N/A

COMPLETED · NCT02405182 · University of Alberta

145 enrolled · 2014-09 · → 2019-03

Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f

Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases

Magnetic Resonance Imaging

📚 Cited Papers (58)

Modulation of apolipoprotein E receptor-2 by ApoE4, amyloid β-peptide, reelin, and secreted amyloid precursor protein: a common point of impact in Alzheimer's disease pathogenesis.

Frontiers in molecular neuroscience (2026) · PMID:41858499

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction.

Neuron (2025) · PMID:39892386

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Protective genetic variants against Alzheimer's disease.

Lancet Neurol (2025) · PMID:40409316

1 figure

Figures

Figures available at source paper.

deep_link

Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion.

Nat Commun (2024) · PMID:39232006

6 figures

Fig. 2

Bioinformatic analysis of the AM-induced VE-cadherin interactome identifies enrichment of secretory and Rho family GTPase pathways. A Gene Ontology (GO) Cell Component and Molecul...

pmc_api

Fig. 3

Comparative analysis of VE-cadherin interactomes identified in whole cell or plasma membrane fractions reveals reproducibly captured proteins and pathways. A Detection of VE-cad-m...

pmc_api

Neurobiology of aging (2009) · PMID:17904250

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses.

The Journal of biological chemistry (2017) · PMID:27994051

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Neuronal migration.

Mech Dev (2001) · PMID:11429281

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation.

Biomolecules (2020) · PMID:32604886

2 figures

Figure 1

Structure of Reelin and its processing fragments: Reelin is a large extracellular matrix protein of 450 kDa. The protein starts with a signal peptide followed by an F-spondin homol...

pmc_api

Figure 2

Modeling of the multiple functions of Reelin during migration, dendritic growth and synaptic development and the corresponding signaling pathways: ( A , A’ ). During the early step...

pmc_api

Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia.

Proceedings of the National Academy of Sciences of the United States of America (2005) · PMID:16113080

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1.

Psychopharmacology (2013) · PMID:23380917

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

Exosomes as nanocarriers for brain-targeted delivery of therapeutic nucleic acids: advances and challenges.

Journal of nanobiotechnology (2025) · PMID:40533746

3 figures

Fig. 1

The structure of the neurovascular section. The neurovascular unit (NVU) comprises neurons, glial cells (astrocytes, microglia, oligodendrocytes), and vascular cells (endothelial c...

pmc_api

Fig. 2

Summary of nanoparticle-based systems, non-invasive approaches, and targeted delivery (TD) in the brain. A The image illustrates seven key methods for overcoming the blood–brain ...

pmc_api

Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereotypies in reeler mutant mice.

Psychopharmacology (2006) · PMID:16783542

1 figure

Figures

Figures available at source paper (no open-access XML found).

deep_link

📙 Related Wiki Pages (15)

࢐ Browse all wiki pages

📓 Linked Notebooks (1)

📓 Selective vulnerability of entorhinal cortex layer II neurons in AD — Analysis Notebook

CI-generated notebook stub for analysis sda-2026-04-01-gap-004. Why do entorhinal cortex layer II stellate neurons die first in AD? Their unique electrophysiological properties, grid cell function, an …

→ Browse all notebooks

⚔ Arena Performance

No arena matches recorded yet. Browse Arenas

→ Browse all arenas & tournaments

📊 Resource Economics & ROI

High Efficiency Resource Efficiency Score

0.81

57.2th percentile (747 hypotheses)

Tokens Used

8,318

KG Edges Generated

273

Citations Produced

Cost Ratios

Cost per KG Edge

71.09 tokens

Lower is better (baseline: 2000)

Cost per Citation

346.58 tokens

Lower is better (baseline: 1000)

Cost per Score Point

13636.07 tokens

Tokens / composite_score

Score Impact

Efficiency Boost to Composite

+0.081

10% weight of efficiency score

Adjusted Composite

0.770

How Economics Pricing Works

Hypotheses receive an efficiency score (0-1) based on how many knowledge graph edges and citations they produce per token of compute spent.

High-efficiency hypotheses (score >= 0.8) get a price premium in the market, pulling their price toward $0.580.

Low-efficiency hypotheses (score < 0.6) receive a discount, pulling their price toward $0.420.

Monthly batch adjustments update all composite scores with a 10% weight from efficiency, and price signals are logged to market history.

Efficiency Price Signals

Date	Signal Price	Score
2026-04-16T20:00	$0.459	0.504

Wiki Pages

Entorhinal Cortex Layer II Neuronscell Entorhinal Cortex Layer IIcell Kyoto Universityinstitution university-of-rochesterinstitution RELN Genegene Metabolomic Biomarkers in Neurodegenerationbiomarker Neuroimaging Biomarkers for Neurodegenerationbiomarker Synaptic Biomarkers in Neurodegenerationbiomarker DNA Methylation Biomarkers in Neurodegenerationbiomarker Blood-Based Biomarkers for Neurodegenerationbiomarker IL-6 (Interleukin-6) in Neurodegenerationbiomarker Glutamate - Excitotoxicity and Neurodegeneration Bbiomarker Liquid Biopsy in Neurodegenerationbiomarker MDS 2026 — Fluid Biomarker Advances in Neurodegeneevent Exosomal Biomarkers in Neurodegenerationbiomarker

KG Entities (45)

Alzheimer's Disease Astrocytic Lactate Shuttle Enhancement f DAB1 Grid Cell-Specific Metabolic Reprogrammi HCN channel / neuronal excitability HCN1 HCN1-Mediated Resonance Frequency Stabil HCN1_channel IDH2 Lactate/monocarboxylate transport MAP6 MCU Microtubule dynamics and stabilization Mitochondrial Calcium Buffering Enhancem Mitochondrial calcium uniporter pathway PGC-1α / mitochondrial biogenesis PGC1A_protein PPARGC1A Perforant Path Presynaptic Terminal Prot RELN

Linked Experiments (3)

Related Hypotheses

TREM2-Dependent Astrocyte-Microglia Cross-talk in Neurodegeneration

Score: 0.990 | neurodegeneration

CYP46A1 Gene Therapy for Age-Related TREM2-Mediated Microglial Senescence Reversal

Score: 0.921 | neurodegeneration

Selective Acid Sphingomyelinase Modulation Therapy

Score: 0.920 | neurodegeneration

HK2-Dependent Metabolic Checkpoint as the Gatekeeper of DAM Transition

Score: 0.919 | neurodegeneration

CYP46A1 Overexpression Gene Therapy

Score: 0.919 | neurodegeneration

Estimated Development

Estimated Cost

Timeline

2.5 years

🧪 Falsifiable Predictions (2)

2 total 0 confirmed 0 falsified

If hypothesis is true, intervention enrich for patients most likely to benefit from neuroprotective intervention

pending conf: 0.50

Expected outcome: enrich for patients most likely to benefit from neuroprotective intervention

Falsified by: Intervention fails to enrich for patients most likely to benefit from neuroprotective intervention

If hypothesis is true, intervention employ an adaptive dose-escalation design starting with 25 μg weekly ICV infusions, escalating to 100 μg based on pharmacokinetic data and safety assessments

pending conf: 0.50

Expected outcome: employ an adaptive dose-escalation design starting with 25 μg weekly ICV infusions, escalating to 100 μg based on pharmacokinetic data and safety assessments

Falsified by: Intervention fails to employ an adaptive dose-escalation design starting with 25 μg weekly ICV infusions, escalating to 100 μg based on pharmacokinetic data and safety assessments

Knowledge Subgraph (115 edges)

▸ Show 16 more

HCN1→IDH2IDH2→MAP6MCU→RELNHCN1→MCUMAP6→MCUMCU→PPARGC1APPARGC1A→RELNHCN1→PPARGC1AMAP6→PPARGC1AHCN1→RELNMAP6→RELNPPARGC1A→SLC16A2MCU→SLC16A2RELN→SLC16A2HCN1→SLC16A2MAP6→SLC16A2

co discussed (41)

RELN→MAP6RELN→HCN1RELN→MCURELN→IDH2MAP6→HCN1

▸ Show 36 more

MAP6→MCUMAP6→IDH2HCN1→MCUHCN1→IDH2MCU→IDH2PPARGC1A→SLC16A2PPARGC1A→RELNPPARGC1A→MAP6PPARGC1A→HCN1PPARGC1A→MCUPPARGC1A→IDH2SLC16A2→RELNSLC16A2→MAP6SLC16A2→HCN1SLC16A2→MCUSLC16A2→IDH2HCN1→MAP6MCU→MAP6IDH2→MAP6RELN→PPARGC1ARELN→SLC16A2HCN1→PPARGC1AHCN1→SLC16A2MCU→PPARGC1AMCU→SLC16A2IDH2→PPARGC1AIDH2→SLC16A2MAP6→SLC16A2MCU→HCN1MCU→RELNMAP6→RELNIDH2→HCN1IDH2→RELNHCN1→RELNIDH2→MCUSLC16A2→PPARGC1A

early vulnerability (1)

entorhinal_cortex_layer_II→alzheimers_disease

enables (2)

microtubule_stabilization→axonal_transportmembrane_resonance→grid_cell_oscillations

encodes (3)

PPARGC1A→PGC1A_proteinRELN→reelin_proteinHCN1→HCN1_channel

implicated in (7)

h-e12109e3→neurodegenerationh-76888762→neurodegenerationh-d2df6eaf→neurodegenerationh-d40d2659→neurodegenerationh-5ff6c5ca→neurodegeneration

▸ Show 2 more

h-57862f8a→neurodegenerationh-aa8b4952→neurodegeneration

mediates (1)

HCN1_channel→membrane_resonance

participates in (7)

MAP6→Microtubule dynamics and stabilizationPPARGC1A→PGC-1α / mitochondrial biogenesisRELN→Reelin signaling / cytoskeletal regulationHCN1→HCN channel / neuronal excitabilitySLC16A2→Lactate/monocarboxylate transport

▸ Show 2 more

IDH2→TCA cycle / metabolic reprogrammingMCU→Mitochondrial calcium uniporter pathway

phosphorylates (1)

reelin_protein→DAB1

prevents (1)

axonal_transport→neurodegeneration_protection

promotes (2)

mitochondrial_biogenesis→perforant_path_protectionDAB1→cytoskeletal_stability

regulates (15)

MAP6→Tau-Independent Microtubule Stabilization via MAP6MAP6→Tau PropagationPPARGC1A→Perforant Path Presynaptic Terminal Protection StrPPARGC1A→Tau PropagationRELN→Reelin-Mediated Cytoskeletal Stabilization Protoco

▸ Show 10 more

RELN→Tau PropagationHCN1→HCN1-Mediated Resonance Frequency Stabilization ThHCN1→Tau PropagationSLC16A2→Astrocytic Lactate Shuttle Enhancement for Grid CeSLC16A2→Tau PropagationIDH2→Grid Cell-Specific Metabolic Reprogramming via IDHIDH2→Tau PropagationMCU→Mitochondrial Calcium Buffering Enhancement via MCMCU→Tau PropagationMAP6→microtubule_stabilization

therapeutic target (7)

Tau-Independent Microtubule Stabilization via MAP6→Alzheimer's DiseasePerforant Path Presynaptic Terminal Protection Str→Alzheimer's DiseaseReelin-Mediated Cytoskeletal Stabilization Protoco→Alzheimer's DiseaseHCN1-Mediated Resonance Frequency Stabilization Th→Alzheimer's DiseaseAstrocytic Lactate Shuttle Enhancement for Grid Ce→Alzheimer's Disease

▸ Show 2 more

Grid Cell-Specific Metabolic Reprogramming via IDH→Alzheimer's DiseaseMitochondrial Calcium Buffering Enhancement via MC→Alzheimer's Disease

Mechanism Pathway for RELN

Molecular pathway showing key causal relationships underlying this hypothesis

graph TD
    RELN["RELN"] -->|encodes| reelin_protein["reelin_protein"]
    RELN_1["RELN"] -->|regulates| Reelin_Mediated_Cytoskele["Reelin-Mediated Cytoskeletal Stabilization Protoco"]
    RELN_2["RELN"] -->|regulates| Tau_Propagation["Tau Propagation"]
    RELN_3["RELN"] -->|participates in| Reelin_signaling___cytosk["Reelin signaling / cytoskeletal regulation"]
    RELN_4["RELN"] -->|co discussed| MAP6["MAP6"]
    RELN_5["RELN"] -->|co discussed| HCN1["HCN1"]
    RELN_6["RELN"] -->|co discussed| MCU["MCU"]
    RELN_7["RELN"] -->|co discussed| IDH2["IDH2"]
    PPARGC1A["PPARGC1A"] -->|co discussed| RELN_8["RELN"]
    SLC16A2["SLC16A2"] -->|co discussed| RELN_9["RELN"]
    RELN_10["RELN"] -->|co discussed| PPARGC1A_11["PPARGC1A"]
    RELN_12["RELN"] -->|co discussed| SLC16A2_13["SLC16A2"]
    MCU_14["MCU"] -->|co discussed| RELN_15["RELN"]
    MAP6_16["MAP6"] -->|co discussed| RELN_17["RELN"]
    IDH2_18["IDH2"] -->|co discussed| RELN_19["RELN"]
    style RELN fill:#ce93d8,stroke:#333,color:#000
    style reelin_protein fill:#4fc3f7,stroke:#333,color:#000
    style RELN_1 fill:#ce93d8,stroke:#333,color:#000
    style Reelin_Mediated_Cytoskele fill:#4fc3f7,stroke:#333,color:#000
    style RELN_2 fill:#ce93d8,stroke:#333,color:#000
    style Tau_Propagation fill:#ffd54f,stroke:#333,color:#000
    style RELN_3 fill:#ce93d8,stroke:#333,color:#000
    style Reelin_signaling___cytosk fill:#81c784,stroke:#333,color:#000
    style RELN_4 fill:#ce93d8,stroke:#333,color:#000
    style MAP6 fill:#ce93d8,stroke:#333,color:#000
    style RELN_5 fill:#ce93d8,stroke:#333,color:#000
    style HCN1 fill:#ce93d8,stroke:#333,color:#000
    style RELN_6 fill:#ce93d8,stroke:#333,color:#000
    style MCU fill:#ce93d8,stroke:#333,color:#000
    style RELN_7 fill:#ce93d8,stroke:#333,color:#000
    style IDH2 fill:#ce93d8,stroke:#333,color:#000
    style PPARGC1A fill:#ce93d8,stroke:#333,color:#000
    style RELN_8 fill:#ce93d8,stroke:#333,color:#000
    style SLC16A2 fill:#ce93d8,stroke:#333,color:#000
    style RELN_9 fill:#ce93d8,stroke:#333,color:#000
    style RELN_10 fill:#ce93d8,stroke:#333,color:#000
    style PPARGC1A_11 fill:#ce93d8,stroke:#333,color:#000
    style RELN_12 fill:#ce93d8,stroke:#333,color:#000
    style SLC16A2_13 fill:#ce93d8,stroke:#333,color:#000
    style MCU_14 fill:#ce93d8,stroke:#333,color:#000
    style RELN_15 fill:#ce93d8,stroke:#333,color:#000
    style MAP6_16 fill:#ce93d8,stroke:#333,color:#000
    style RELN_17 fill:#ce93d8,stroke:#333,color:#000
    style IDH2_18 fill:#ce93d8,stroke:#333,color:#000
    style RELN_19 fill:#ce93d8,stroke:#333,color:#000

3D Protein Structure

🧬 RELN — PDB 5ES4 Click to expand 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll | Reset: right-click

Source Analysis

Selective vulnerability of entorhinal cortex layer II neurons in AD

neurodegeneration | 2026-04-01 | completed

Community Feedback

0 0 upvotes · 0 downvotes

💬 0 comments ⚠ 0 flags ✏ 0 edit suggestions

No comments yet. Be the first to comment!

View all feedback (JSON)

Same Analysis (5)

Perforant Path Presynaptic Terminal Protection Strategy

Score: 0.70 · PPARGC1A

Mitochondrial Calcium Buffering Enhancement via MCU Modulation

Score: 0.65 · MCU

HCN1-Mediated Resonance Frequency Stabilization Therapy

Score: 0.65 · HCN1

Grid Cell-Specific Metabolic Reprogramming via IDH2 Enhancement

Score: 0.65 · IDH2

Tau-Independent Microtubule Stabilization via MAP6 Enhancement

Score: 0.57 · MAP6

→ View all analysis hypotheses

Reelin-Mediated Cytoskeletal Stabilization Protocol

Description

Mechanistic Overview

Mechanistic Overview

Molecular and Cellular Rationale

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

Curated Mechanism Pathway

Dimension Scores

✓ Supporting Evidence 13

✗ Opposing Evidence 11

Novel Therapeutic Hypotheses for Entorhinal Cortex Layer II Selective Vulnerability in AD

1. HCN1-Mediated Resonance Frequency Stabilization Therapy

Critical Evaluation of EC Layer II Therapeutic Hypotheses

1. HCN1-Mediated Resonance Frequency Stabilization Therapy

Druggability Assessment of EC Layer II Therapeutic Hypotheses

HYPOTHESIS 3: Reelin-Mediated Cytoskeletal Stabilization (Revised Confidence: 0.55)

Druggability Assessment: MODERATE-LOW

Price History

Clinical Trials (10) Relevance: 68%

📚 Cited Papers (58)

📙 Related Wiki Pages (15)

📓 Linked Notebooks (1)

⚔ Arena Performance

🔄 Related Hypotheses

Same Analysis (5)

🧬 Same Target Gene / Disease (30)

📊 Resource Economics & ROI

Cost Ratios

Score Impact

How Economics Pricing Works

Efficiency Price Signals

Wiki Pages

KG Entities (45)

Linked Experiments (3)

Related Hypotheses

Estimated Development

🧪 Falsifiable Predictions (2)

Knowledge Subgraph (115 edges)

activates (1)

associated with (5)

co associated with (21)

co discussed (41)

early vulnerability (1)

enables (2)

encodes (3)

implicated in (7)

mediates (1)

participates in (7)

phosphorylates (1)

prevents (1)

promotes (2)

regulates (15)

therapeutic target (7)

Mechanism Pathway for RELN

3D Protein Structure

Source Analysis

Selective vulnerability of entorhinal cortex layer II neurons in AD

Community Feedback

Same Analysis (5)