TREM2 Agonist Antibody Rescue of Astrocyte-Microglia Signalling in 5xFAD Mice

In_Vivo Score: 0.794 Price: $0.50 Alzheimer's disease 5xFAD transgenic mice (n=15/group x 4 groups: WT-vehicle, 5xFAD-vehicle, 5xFAD-AL002c low, 5xFAD-AL002c high) Status: proposed

What This Experiment Tests

In_Vivo experiment designed to assess clinical efficacy targeting TREM2 in 5xFAD transgenic mice (n=15/group x 4 groups: WT-vehicle, 5xFAD-vehicle, 5xFAD-AL002c low, 5xFAD-AL002c high). Primary outcome: Reduction of astrocyte A1 markers (C3, Lcn2 mRNA) >=40% vs 5xFAD-vehicle; NOR discrimination index >

Description

Test whether a TREM2-agonist antibody (AL002c analogue) normalises the dysfunctional astrocyte-microglia cross-talk that amplifies neuroinflammation in 5xFAD mice. Weekly IV injections (10 mg/kg) from 3 to 9 months of age; endpoint readouts at 9 months include LPS-stimulated astrocyte A1-marker expression (C3, Lcn2), microglial plaque-associated gene scores (Cst7, Spp1), soluble Abeta42/Abeta40 ratio, and NOR cognitive test.

TARGET GENE

TREM2 (Score: 0.628)

MODEL SYSTEM

5xFAD transgenic mice (n=15/group x 4 groups: WT-vehicle, 5xFAD-vehicle, 5xFAD-AL002c low, 5xFAD-AL002c high)

ESTIMATED COST

$85,000

TIMELINE

18 months

PATHWAY

TREM2/DAP12 -> PI3K/AKT -> astrocyte A1 polarisation

SOURCE

task:a989715e-c687-4558-91ca-74fce1474bd2

PRIMARY OUTCOME

Reduction of astrocyte A1 markers (C3, Lcn2 mRNA) >=40% vs 5xFAD-vehicle; NOR discrimination index >=0.65

Scoring Dimensions

Protocol

Breed 5xFAD hemizygous x C57BL/6J; genotype at P21. 2. Randomise to 4 groups at 3 months (n=15/group, sex-balanced). 3. Administer AL002c-analogue or vehicle IV weekly (3-9 months). 4. Monthly behavioural: NOR, open field. 5. Sacrifice at 9 months; isolate cortical microglia (CD11b+) and astrocytes (GFAP+) by FACS. 6. Bulk RNA-seq on sorted populations; ELISA for Abeta42/40; IHC plaque burden. 7. Primary endpoint: fold-change in A1 marker panel (C3, Lcn2, H2-D1); secondary: plaque load, NOR score, microglial DAM signature.

Expected Outcomes

AL002c-analogue will suppress astrocyte A1 conversion by >=40% (C3, Lcn2), shift microglia toward DAM-protective state (increased Cst7, Spp1), reduce plaque burden by ~25%, and restore NOR discrimination index to >=0.65.

Success Criteria

Primary: >=40% reduction in C3 mRNA in GFAP+ astrocytes (Student t-test p<0.05). Secondary: NOR discrimination index >=0.65 (vs ~0.50 vehicle); >=15% plaque area reduction.

Related Hypotheses (6)

TREM2-Mediated Astrocyte-Microglia Cross-Talk in Neurodegeneration0.642

AD fine-mapping identifies causal variants in microglia-specific enhancers with small credible sets0.000

TREM2-Dependent Astrocyte-Microglia Cross-talk in Neurodegeneration0.990

TREM2-Mediated Astrocyte-Microglia Cross-Talk in Neurodegeneration0.907

H1: TREM2 Agonism to Redirect APOE4-Enhanced Microglia from Synapse Pruning to Amyloid Clearance0.904

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