Constitutive neuronal AMPK activation via AAV9-Synapsin-AMPKα1(T172D) tests whether restoring AMPK activity reverses microglial inflammation after it is established. Requires post-onset rescue design (inducible system) rather than pre-symptomatic prevention to answer the therapeutic reversibility gap. Acts upstream of lipid synthesis to normalize the neuronal-microglial lipid transfer axis.
Curated pathway from expert analysis
flowchart TD A["AMPK alpha Complex<br/>PRKAA1/PRKAA2 Energy Sensor"] B["ATP Stress Detection<br/>AMP-to-ATP Ratio Shift"] C["ULK1 and Autophagy Activation<br/>Cellular Recovery Program"] D["mTORC1 Restraint<br/>Anabolic Pressure Reduced"] E["Inflammation Resolution Support<br/>Metabolic Rebalancing"] F["Post-onset Neuronal Rescue<br/>Reversibility Test Readout"] A --> B B --> C B --> D C --> E D --> E E --> F style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7 style E fill:#1b5e20,stroke:#81c784,color:#81c784 style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for PRKAA1/PRKAA2 (AMPKα1/α2) 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 PRKAA1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF AAV9-Synapsin-AMPKα1(T172D) is delivered via inducible expression to 6-month-old 5xFAD mice (post-onset of amyloid pathology), THEN microglial CD68+ area fraction in cortex will decrease by ≥40% re | ≥40% reduction in cortical CD68+ immunoreactive area fraction | — no observation — | pending | 0.65 |
| IF neuronal AMPK restoration (post-onset) reduces microglial pro-inflammatory cytokine (IL-1β, TNF-α) levels in 5xFAD cortex, THEN pharmacological blockade of SREBP-mediated lipogenesis using fatostat | IL-1β and TNF-α protein levels remain elevated (no significant reduction) in the fatostatin + AMPK group compared to vehicle, while AMPK alone shows ≥30% cytoki | — no observation — | pending | 0.45 |