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TREM2 KO amyloid pathology study

Validation Score: 0.750 Price: $0.50 Alzheimers Disease Mouse (5xFAD/TREM2-/-) Status: in_progress

What This Experiment Tests

Validation experiment designed to validate causal mechanisms targeting TREM2 in Mouse (5xFAD/TREM2-/-). Measures changes in biological function and validates hypothesis predictions.

Description

Measure synaptic density (PSD-95/vGlut1 immunofluorescence) and electrophysiological LTP in hippocampal slices from 5xFAD/TREM2-/- mice.

TARGET GENE
MODEL SYSTEM
Mouse (5xFAD/TREM2-/-)
ESTIMATED COST
$0
TIMELINE
0 months
PATHWAY
N/A
SOURCE
N/A

Scoring Dimensions

Info Gain 0.00 (25%) Feasibility 0.00 (20%) Hyp Coverage 0.00 (20%) Cost Effect. 0.00 (15%) Novelty 0.00 (10%) Ethical Safety 0.00 (10%) 0.750 composite

📖 Wiki Pages

TREM2-Mediated Amyloid Clearance PathwaypathwayTREM2 Microglial Signaling Pathway in NeurodegenermechanismTREM2 in ALSmechanismTREM2 Agonists in Alzheimer DiseasetherapeuticTREM2 Mechanism HubmechanismTREM2 Microglial Priming Inhibitor for Pre-SymptomideaTREM2 Inflammatory Cytokine RegulationmechanismTREM2 in Frontotemporal DementiamechanismTREM2 Agonist Therapy for Parkinson's Disease — ExexperimentTREM2 Therapeutics Investment LandscapeinvestmentTREM2 Protein (Triggering Receptor Expressed on MyentityTREM2-Deficient MicrogliacellTREM2 in Amyotrophic Lateral Sclerosismechanismtrem2-alpha-synuclein-clearance-parkinsonsgeneralTREM2 Genegene

Protocol

Protocol: TREM2 KO Amyloid Pathology Validation Study

Study Design


Parallel-group comparison of 5xFAD transgenic mice with and without TREM2 knockout (5xFAD/TREM2-/- vs 5xFAD/TREM2+/+) to assess amyloid burden.

Animals and Genotyping

  • Use 5xFAD/TREM2-/- double mutant mice (n=10 per group) and 5xFAD/TREM2+/+ controls (n=10 per group)
  • Confirm genotype by PCR from tail biopsies at weaning (3 weeks)
  • Harvest tissue at 6 months (peak amyloid deposition) and 9 months (severe pathology)
  • Equal sex distribution per group (5M/5F)

    • ...

    Expected Outcomes

    Expected Outcomes

    Primary Outcomes

  • Increased amyloid burden in TREM2-/- mice: TREM2 KO mice are expected to show 30–60% greater plaque coverage vs TREM2+/+ 5xFAD mice at 6 months based on published literature (Wang et al. 2015; Jay et al. 2015)
  • Increased plaque number and size: TREM2 KO expected to increase diffuse/immature plaque count; compaction (Thioflavin-S) may be reduced
  • Accelerated temporal progression: Differences expected to be larger at 9 months than 6 months

    • ...

    Success Criteria

    Success Criteria

    Primary

    • [ ] ≥30% increase in cortical Aβ % area coverage in 5xFAD/TREM2-/- vs 5xFAD/TREM2+/+ (p < 0.05)
    • [ ] ≥30% increase in hippocampal Aβ % area coverage (p < 0.05)
    • [ ] Effect reproduces in both 6-month and 9-month cohorts

    Secondary

    • [ ] Thioflavin-S+ plaque density quantified in both groups
    • [ ] IBA1 microglial density around plaques quantified
    • [ ] All controls pass QC (positive shows >10% area, negative shows <0.5% area)

    ...

    Related Hypotheses (9)

    TREM2-Dependent Microglial Senescence Transition0.905
    TREM2-mediated microglial tau clearance enhancement0.800
    Cell-Type Specific TREM2 Upregulation in DAM Microglia0.761
    TREM2-Mediated Selective Aggregate Clearance Pathway0.699
    TREM2 Conformational Stabilizers for Synaptic Discrimination0.685

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