Aβ initiates tau missorting, but persistent degeneration is then maintained by activated microglia through C1q/C3-CR3-mediated pruning and inflammatory remodeling. This model best explains continued synapse loss after amyloid reduction, though it may maintain degeneration more clearly than tau polarity failure itself.
Curated pathway from expert analysis
flowchart TD
A["C1Q Deficiency<br/>Impaired Clearance of Apoptotic Cells"]
B["C1QC Assembly<br/>Heterocomplex Formation"]
C["Synaptic Pruning Dysregulation<br/>Unpruned Connections"]
D["Microglial Overactivation<br/>Complement Deposition"]
E["C3b/C4b Deposition<br/>Neuronal Surface"]
F["Synaptic Loss<br/>Excessive Pruning in AD"]
G["Long-Term Potentiation<br/>Memory Formation Impaired"]
H["Cognitive Decline<br/>AD-Related Dementia"]
A --> B
B --> C
B --> D
C --> F
D --> E
E --> F
F --> G
G --> H
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for C1QA,C1QB,C1QC,C3,ITGAM,TREM2,TYROBP from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for C1QA,C1QB,C1QC,C3,ITGAM,TREM2,TYROBP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF C1q/C3-CR3-mediated microglial pruning sustains synapse loss after tau missorting is established, THEN pharmacologically blocking CR3 (ITGAM) with a selective antagonist 3 months after Aβ42 oligome | Hippocampal CA1 synapse density will increase by ≥25% (measured by PSD95+VGluT1 colocalization via confocal microscopy) in CR3-blocked mice relative to vehicle- | — no observation — | pending | 0.65 |
| IF microglia activation is the obligate maintenance mechanism for post-Aβ neurodegeneration independent of tau polarity failure, THEN conditional knockout of TREM2/TYROBP specifically after tau missor | CSF neurofilament light chain (NfL) levels will stabilize (change <5%/month) in P301S;TREM2-cKO mice after tamoxifen-induced knockout, while P301S;TREM2-WT mice | — no observation — | pending | 0.58 |