Membrane Cholesterol Gradient Modulators
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From Analysis:
Lipid raft composition changes in synaptic neurodegeneration
Investigate how lipid raft composition (cholesterol metabolism, sphingolipids) changes in synaptic membranes during neurodegeneration and their mechanistic role in amyloid-beta processing and synapse dysfunction
Description
Mechanistic Overview
Membrane Cholesterol Gradient Modulators starts from the claim that modulating ABCA1/LDLR/SREBF2 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Membrane Cholesterol Gradient Modulators: Precision Lipid Therapeutics Overview and Conceptual Innovation Membrane cholesterol distribution is not uniform across neuronal compartments. Lipid rafts at synaptic terminals contain 40-50% cholesterol, while non-raft membrane regions contain 20-30%. This cholesterol gradient is essential for proper receptor clustering, signal transduction, and neurotransmitter release....
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Curated Mechanism Pathway
Curated pathway diagram from expert analysis
flowchart TD
A["Neuronal Membrane Cholesterol Pools"] --> B{"Lipid Raft Domains 40-50%"}
A --> C{"Non-Raft Regions 20-25%"}
B --> D["APP/BACE1 Co-localization"]
D --> E["Amyloidogenic Processing"]
E --> F["Abeta Production"]
B --> G["Tau Kinase Activation"]
G --> H["GSK-3beta/CDK5 at Rafts"]
H --> I["Tau Hyperphosphorylation"]
J["ABCA1 Activator"] -->|"Modulates"| B
K["LDLR Modulator"] -->|"Regulates"| A
L["SREBF2 Inhibitor"] -->|"Controls"| A
M["Precision Cholesterol Gradient Modulators"] --> J
M --> K
M --> L
C --> N["Non-Raft alpha-Secretase"]
N --> O["Non-Amyloidogenic Processing"]
P["Pathological Raft Inversion >60%"] --> Q["Synaptic Dysfunction"]
B -->|"Dysregulation"| P
style B fill:#ef5350
style F fill:#ef5350
style I fill:#ef5350
style P fill:#ef5350
style Q fill:#ef5350
style M fill:#81c784
style O fill:#81c784
style N fill:#ffd54f
style J fill:#ce93d8
style K fill:#ce93d8
style L fill:#ce93d8
GTEx v10 Brain Expression
JSONMedian TPM across 13 brain regions for ABCA1/LDLR/SREBF2 from GTEx v10.
Dimension Scores
Legacy Card View — expandable citation cards
✓ Supporting Evidence 14
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microgl
Cyclodextrins reduce amyloid pathology but can impair synaptic function through non-selective cholesterol depl… HIGH▼
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin i
Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further investigations to elucidate the detailed roles and molecular mechanisms of TREM2 in microglial responses. A major breakthrough in our understanding of TREM2 is based on our hypothesis suggesting that TREM2 may act as a multifaceted player in microglial functions in AD brain homeostasis. We conclude that TREM2 can not only influence microglial functions in amyloid and tau pathologies but also participate in inflammatory responses and metabolism, acting alone or with other molecules, such as apolipopro
Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive
Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils
Lipid raft disruption with methyl-β-cyclodextrin reduces BACE1-APP co-localization and Aβ generation by 40% in… HIGH▼
Recent studies have demonstrated that aberrant sister chromatid cohesion causes genomic instability and hence is responsible for the development of a tumor. The Chl1 (chromosome loss 1) protein (homolog of human ChlRl/DDX11 helicase) plays an essential role in the proper segregation of chromosomes during mitosis. The helicase activity of Chl1 is critical for sister chromatid cohesion. Our study demonstrates that Hsp90 interacts with Chl1 and is necessary for its stability. We observe that the Hsp90 nonfunctional condition (temperature-sensitive iG170Dhsp82 strain at restrictive temperature) induces proteasomal degradation of Chl1. We have mapped the domains of Chl1 and identified that the presence of domains II, III, and IV is essential for efficient interaction with Hsp90. We have demonstrated that Hsp90 inhibitor 17-AAG (17-allylamino-geldenamycin) causes destabilization of Chl1 protein and enhances significant disruption of sister chromatid cohesion, which is comparable to that obse
ABCA1 upregulation by LXR agonists redistributes cholesterol from rafts, reducing amyloid processing without g… HIGH▼
INTRODUCTION: This study was conducted to compare parameters of kidney injury, oxidative stress and inflammation in people with diabetic nephropathy (DN) and type 2 diabetes mellitus (T2DM). METHODS: In a cross-sectional study, 57 cases with DN and 57 cases with T2DM were included in the study. Fasting blood samples were obtained to determine parameters of kidney injury, oxidative stress and inflammation. RESULTS: The current study showed that patients with DN had higher tumor necrosis factor-α (TNF-α) (167.0 ± 40.1 vs. 151.4 ± 37.4 ng/L, P < .05) and matrix metalloproteinase-2 (MMP-2) concentrations (1625.2 ± 631.0 vs. 1391.5 ± 465.4 ng/mL, P < .05) compared with T2DM cases. Moreover, we observed a non-significant increase in MMP-9 levels among patients with DN compared with individuals with T2DM (4864.4 ± 1934.3 vs. 4239.2 ± 1853.9 ng/L, P > .05). Furthermore, advanced glycation end products (AGEs) levels in patients with DN were higher than that of patients with T2DM (8511.7 ± 1799.
Engineered HDL nanoparticles selectively extract raft cholesterol and reduce cerebral amyloid angiopathy in AP… MEDIUM▼
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused a devastating health crisis worldwide. In this review, we have discussed that prophylactic phytochemical quercetin supplementation in the form of foods or nutraceuticals may help manage the COVID-19 pandemic. The following evidence supports our argument. First, nuclear factor erythroid-derived 2-like 2 (NRF2) agonists abrogate replication of SARS-CoV-2 in lung cells, and quercetin is a potent NRF2 agonist. Second, quercetin exerts antiviral activity against several zoonotic coronaviruses, including SARS-CoV-2, mainly by inhibiting the entry of virions into host cells. Third, inflammatory pathways activated by nuclear factor kappa B, inflammasome, and interleukin-6 signals elicit cytokine release syndrome that promotes acute respiratory distress syndrome in patients with COVID-19, and quercetin inhibits these pro-inflammatory signals. Fourth, patie
Flotillin-1 knockdown disrupts amyloidogenic lipid raft platforms and reduces Aβ42 secretion by 55% in human i… HIGH▼
Plants are exposed to environments that fluctuate of timescales varying from seconds to months. Leaves that develop in one set of conditions optimise their metabolism to the conditions experienced, in a process called developmental acclimation. However, when plants experience a sustained change in conditions, existing leaves will also acclimate dynamically to the new conditions. Typically this process takes several days. In this review, we discuss this dynamic acclimation process, focussing on the responses of the photosynthetic apparatus to light and temperature. We briefly discuss the principal changes occurring in the chloroplast, before examining what is known, and not known, about the sensing and signalling processes that underlie acclimation, identifying likely regulators of acclimation.
Isolation of detergent resistant microdomains from cultured neurons: detergent dependent alterations in protei… MEDIUM▼
BACKGROUND: Membrane rafts are small highly dynamic sterol- and sphingolipid-enriched membrane domains that have received considerable attention due to their role in diverse cellular functions. More recently the involvement of membrane rafts in neuronal processes has been highlighted since these specialized membrane domains have been shown to be involved in synapse formation, neuronal polarity and neurodegeneration. Detergent resistance followed by gradient centrifugation is often used as first step in screening putative membrane raft components. Traditional methods of raft isolation employed the nonionic detergent Triton X100. However successful separation of raft from non-raft domains in cells is dependent on matching the detergent used for raft isolation to the specific tissue under investigation. RESULTS: We report here the isolation of membrane rafts from primary neuronal culture using a panel of different detergents that gave rise to membrane fractions that differed in respect to
Accumulation of exogenous amyloid-beta peptide in hippocampal mitochondria causes their dysfunction: a protect… MEDIUM▼
Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin red
Association of a photoreceptor-specific tetraspanin protein, ROM-1, with triton X-100-resistant membrane rafts… MEDIUM▼
This study reports the isolation and characterization of a Triton X-100-resistant membrane fraction from homogenates of rod outer segment (ROS) disk membranes purified free of the surrounding plasma membrane. A portion of the ROS disk membrane was found to be resistant to Triton X-100 extraction at 4 degrees C. This detergent-resistant fraction was isolated as a low buoyant density band on sucrose density gradients and exhibited an increase in light scattering detected at 600 nm. Biochemical analysis of the Triton X-100-resistant fraction showed it to be enriched in cholesterol and sphingomyelin relative to phospholipid and in phospholipid relative to protein compared with the soluble fraction. The Triton X-100-resistant membranes described herein did not arise simply from partial solubilization of the ROS disk membranes because detergent-treated low buoyant density fractions isolated from homogenates with octyl glucopyranoside had cholesterol and sphingomyelin content indistinguishabl
Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid ra… MEDIUM▼
Gangliosides are considered to be involved in the maintenance and repair of nervous tissues. Recently, novel roles of gangliosides in the regulation of complement system were reported by us. In this study, we compared complement activation, inflammatory reaction and disruption of glycolipid-enriched microdomain (GEM)/rafts among various mutant mice of ganglioside synthases, i.e. GM2/GD2 synthase knockout (KO), GD3 synthase KO, double KO (DKO) of these two enzymes and wild type. Up-regulation of complement-related genes, deposits of C1q, proliferation of astrocytes and infiltration of microglia also showed similar gradual severity depending on the defects in ganglioside compositions. In the expression of inflammatory cytokines such as IL-1β and tumor necrosis factor α, only DKO showed definite up-regulation. Immunoblotting of fractions from sucrose density gradient ultracentrifugation revealed that lipid raft markers such as caveolin-1 and flotillin-1 tended to disperse from the raft fr
✗ Opposing Evidence 10
Non-selective cholesterol depletion impairs LTP and spatial memory through disruption of NMDA receptor raft lo… HIGH▼
Silica nanopores have electron channels and ion channels interpenetrating each other, which prompt the use of this structure for creating efficient electronic devices. In this study, silica nanopores membrane modified screen printed electrodes were applied in a smartphone-based electrochemiluminescence system for nitroaromatic explosives detection. Universal serial bus-on the go (USB-OTG) and camera on smartphone were used as the electrical stimulation and luminescence capture, respectively. ⎕Multimode methods including (red-green-blue) RGB, (hue-saturation-brightness) HSB, and Gray were proposed for luminescence analysis. Specific polypeptides were immobilized on the nanopores modified electrodes for nitroaromatic explosives sensing. With positive-charged tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)32+) as electrochemiluminescence label, the increase in luminescence was associated with the selective ion channels and the well-conductive electron channels in the negative-charged nanopores
Raft cholesterol is essential for insulin receptor signaling in neurons; depletion induces insulin resistance … HIGH▼
Cyclodextrin-based cholesterol extraction shows poor selectivity between raft and non-raft domains in vivo, ac… MEDIUM▼
Chronic raft perturbation accelerates tau phosphorylation via GSK-3β activation in cholesterol-depleted membra… MEDIUM▼
Blood-brain barrier penetration of cyclodextrin conjugates remains limited (<5% bioavailability) even with tar… HIGH▼
OBJECTIVE: To assess public awareness regarding endodontic treatment and assess patients' knowledge regarding endodontic treatment. MATERIALS AND METHODS: A questionnaire was prepared and given to 300 patients who had visited the Department of Conservative Dentistry and Endodontics between November 2021 and October 2022, after obtaining ethical clearance and consent from all the participants. The questionnaire included sociodemographic details and about their knowledge about endodontic treatment. The collected data were tabulated and analyzed. STATISTICAL ANALYSIS: Data analysis was performed using methods of descriptive statistics like frequency and percentages. RESULTS: We found that most of the respondents had an average level of knowledge regarding endodontic treatment. CONCLUSION: We observed an improvement in knowledge and perception regarding endodontic treatment.
Sphingomyelin-cholesterol interactions in lipid rafts show cooperative binding — selective cholesterol removal… HIGH▼
Isolated trapezio-metacarpal joint dislocation is a rare injury. Despite being simple to reduce, there is not yet a consensus regarding how to secure the reduction, the type of immobilization, and the postoperative protocol. Herein, we present a rare case of pure trapezio-metacarpal joint dislocation without any associated fractures that was treated with closed reduction and intermetacarpal fixation, six weeks of immobilization, and an early rehabilitation protocol.
Oxysterol intermediates generated during cholesterol mobilization are neurotoxic at nanomolar concentrations, … MEDIUM▼
BACKGROUND: Insertion of laryngeal mask airway (LMA) with propofol in children may cause hypotension, laryngospasm and apnoea. Ketamine and fentanyl have been combined separately with propofol to prevent depression of cardiovascular system during LMA insertion, especially in paediatric patients. Ketamine-fentanyl and propofol-fentanyl combinations have analgesic effect, prevent coughing and apnoea and regarded as agents of choice for LMA insertions. However, the cardiovascular effects of the two admixtures for LMA insertions have not been fully assessed in children. We compared the haemodynamic effects of ketamine-fentanyl and propofol-fentanyl combinations for LMA insertion in paediatric patients who underwent herniotomy in our facility. PATIENTS AND METHODS: This comparative study was conducted on 80 children aged 1-15 years, ASA physical Statuses I and II, who had herniotomy under general anaesthesia. The patients were randomised into two groups (A and B) of 40 patients each and LMA
Astrocyte-neuron cholesterol shuttling via apoE lipoproteins operates at timescales of hours — acute cholester… MEDIUM▼
Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, ev
ABCA1 and ABCA7 share overlapping substrate specificity — selective ABCA1 inhibition without affecting ABCA7 h… HIGH▼
Pap tests are still underutilized by minority women due to limited awareness of cervical cancer screening (CCS), inadequate health care access, and cultural or religious beliefs. Human papillomavirus (HPV) self-sampling, a new CCS tool, has demonstrated potential to overcome some of these barriers. In 2021, women aged 30-65 years old were recruited across Minnesota to complete an online survey. The survey assessed five outcome measures related to HPV self-sampling: (1) awareness of test; (2) self-efficacy to conduct test; (3) location preference of test (clinic vs. home); 4) collector preference (self vs. clinician); and (5) preference of CCS strategy (HPV self-sampling vs. Pap test). Modified Poisson regressions tested associations between sociodemographic variables and outcomes. A total of 420 women completed the survey, of which 32.4% identified as Non-Hispanic white, 22.2% as Hispanic, 12.6% as Black/African-American, 28.3% as Asian, 1.9% as American Indian/Alaskan Native, and 1.4%
Phase II trial of 2-hydroxypropyl-β-cyclodextrin in NPC showed hepatotoxicity and ototoxicity at CNS-relevant … HIGH▼
During the metagenomics era, high-throughput sequencing efforts both in mice and humans indicate that non-coding RNAs (ncRNAs) constitute a significant fraction of the transcribed genome. During the past decades, the regulatory role of these non-coding transcripts along with their interactions with other molecules have been extensively characterized. However, the study of long non-coding RNAs (lncRNAs), an ncRNA regulatory class with transcript lengths that exceed 200 nucleotides, revealed that certain non-coding transcripts are transcriptional "by-products", while their loci exert their downstream regulatory functions through RNA-independent mechanisms. Such mechanisms include, but are not limited to, chromatin interactions and complex promoter-enhancer competition schemes that involve the underlying ncRNA locus with or without its nascent transcription, mediating significant or even exclusive roles in the regulation of downstream target genes in mammals. Interestingly, such RNA-indep
🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼
Theoretical Analysis: Membrane Cholesterol Gradient Modulators in Neurodegeneration
Key Molecular Mechanisms
The hypothesis centers on three interconnected nodes controlling neuronal cholesterol distribution:
🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼
Critical Evaluation
Key Weaknesses
1. Mechanistic Specificity Gap
The hypothesis invokes three interconnected but functionally distinct nodes without clearly specifying which pathological cascade is the primary therapeutic target. Is the goal amyloid clearance, synaptic repair, or neuroinflammation modulation? The predictions list these as independent outcomes rather than mechanistically linked events. This ambiguity weakens testability—a robust hypothesis should generate predictions about which process, when, and in what sequence.
2. Causal vs. Correlational Evidence
The
🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼
Practical and Translational Assessment: Membrane Cholesterol Gradient Modulators
Druggability Analysis
The three nodes—ABCA1, LDLR, and SREBF2—present variable tractability. SREBF2, as a transcription factor, is notoriously difficult to target with small molecules; while compounds like fatostatin (Sigma-Aldrich) inhibit SREBP processing in vitro, no CNS-penetrant clinical candidate exists. ABCA1 modulators (e.g., avasimibe, implitapide) have been explored but face challenges: peripheral upregulation causes hepatomegaly and lipogenesis—exactly the toxicity that derailed L
⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼
{"hypothesis_title":"Membrane Cholesterol Gradient Modulators for Neurodegeneration","synthesis_summary":"The hypothesis proposes targeting cholesterol homeostasis in neurodegeneration through three interconnected nodes (ABCA1, LDLR, SREBF2), but faces significant translational challenges. While the biological rationale is strong—neuronal cholesterol dysregulation is well-documented in AD and PD—the mechanistic specificity gap and druggability limitations substantially weaken therapeutic feasibility. The most critical barrier is achieving CNS-penetrant modulation without peripheral toxicity,
Price History
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| ⚖ | Recalibrated | $0.517 | ▼ 1.1% | 2026-04-12 18:34 | |
| ⚖ | Recalibrated | $0.523 | ▼ 0.2% | 2026-04-12 10:15 | |
| ⚖ | Recalibrated | $0.524 | ▼ 1.8% | 2026-04-12 05:13 | |
| ⚖ | Recalibrated | $0.533 | ▼ 0.5% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.536 | ▲ 0.6% | 2026-04-10 15:53 | |
| ⚖ | Recalibrated | $0.533 | ▼ 8.9% | 2026-04-08 18:39 | |
| ⚖ | Recalibrated | $0.585 | ▲ 3.2% | 2026-04-06 04:04 | |
| ⚖ | Recalibrated | $0.567 | ▼ 1.0% | 2026-04-04 16:38 | |
| ⚖ | Recalibrated | $0.573 | ▲ 1.7% | 2026-04-04 16:02 | |
| ⚖ | Recalibrated | $0.563 | ▼ 0.8% | 2026-04-04 01:39 | |
| ⚖ | Recalibrated | $0.567 | ▼ 24.7% | 2026-04-03 23:46 | |
| ⚖ | Recalibrated | $0.754 | ▲ 5.2% | market_dynamics | 2026-04-03 01:06 |
| ⚖ | Recalibrated | $0.717 | ▲ 19.8% | market_dynamics | 2026-04-03 01:06 |
| ⚖ | Recalibrated | $0.598 | ▲ 3.8% | 2026-04-02 21:55 | |
| ⚖ | Recalibrated | $0.577 | ▼ 0.6% | market_recalibrate | 2026-04-02 19:14 |
Clinical Trials (3) Relevance: 4%
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📚 Cited Papers (48)
📅 Citation Freshness Audit
Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
No citation freshness data yet. Export bibliography — run scripts/audit_citation_freshness.py to populate.
📙 Related Wiki Pages (15)
📓 Linked Notebooks (7)
📊 Resource Economics & ROI
Cost Ratios
Score Impact
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 | $0.511 | 0.580 |
📋 Reviews View all →
Structured peer reviews assess evidence quality, novelty, feasibility, and impact. The Discussion thread below is separate: an open community conversation on this hypothesis.
💬 Discussion
No DepMap CRISPR Chronos data found for ABCA1/LDLR/SREBF2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
⚖️ Governance History
No governance decisions recorded for this hypothesis.
Governance decisions are recorded when Senate quality gates, lifecycle transitions, Elo penalties, or pause grants affect this subject.
Wiki Pages
KG Entities (48)
Linked Experiments (1)
Related Hypotheses
Estimated Development
🧪 Falsifiable Predictions (5)
Knowledge Subgraph (169 edges)
associated with (13)
causes (1)
co associated with (14)
co discussed (102)
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interacts with (10)
involved in (6)
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modifies (3)
participates in (11)
regulates (4)
Mechanism Pathway for ABCA1/LDLR/SREBF2
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
h_9d29bfe5["h-9d29bfe5"] -->|targets| ABCA1_LDLR_SREBF2["ABCA1/LDLR/SREBF2"]
ABCA1_LDLR_SREBF2_1["ABCA1/LDLR/SREBF2"] -->|associated with| neurodegeneration["neurodegeneration"]
ABCA1_LDLR_SREBF2_2["ABCA1/LDLR/SREBF2"] -->|co associated with| FLOT1["FLOT1"]
ABCA1_LDLR_SREBF2_3["ABCA1/LDLR/SREBF2"] -->|co associated with| SGMS1_SGMS2["SGMS1/SGMS2"]
ABCA1_LDLR_SREBF2_4["ABCA1/LDLR/SREBF2"] -->|co associated with| BACE1["BACE1"]
ABCA1_LDLR_SREBF2_5["ABCA1/LDLR/SREBF2"] -->|co associated with| CYP46A1["CYP46A1"]
ABCA1_LDLR_SREBF2_6["ABCA1/LDLR/SREBF2"] -->|co associated with| ST3GAL2_ST8SIA1["ST3GAL2/ST8SIA1"]
ABCA1_LDLR_SREBF2_7["ABCA1/LDLR/SREBF2"] -->|involved in| cholesterol_efflux___lipi["cholesterol_efflux___lipid_transport"]
style h_9d29bfe5 fill:#4fc3f7,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2 fill:#ce93d8,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_1 fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_2 fill:#ce93d8,stroke:#333,color:#000
style FLOT1 fill:#ce93d8,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_3 fill:#ce93d8,stroke:#333,color:#000
style SGMS1_SGMS2 fill:#ce93d8,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_4 fill:#ce93d8,stroke:#333,color:#000
style BACE1 fill:#ce93d8,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_5 fill:#ce93d8,stroke:#333,color:#000
style CYP46A1 fill:#ce93d8,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_6 fill:#ce93d8,stroke:#333,color:#000
style ST3GAL2_ST8SIA1 fill:#ce93d8,stroke:#333,color:#000
style ABCA1_LDLR_SREBF2_7 fill:#ce93d8,stroke:#333,color:#000
style cholesterol_efflux___lipi fill:#81c784,stroke:#333,color:#000
3D Protein Structure
🧬 ABCA1 — PDB 7TBJ Click to expand 3D viewer
Source Analysis
Lipid raft composition changes in synaptic neurodegeneration
neurodegeneration | 2026-04-01 | completed
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