Age-related decline in lysosomal function contributes to the accumulation of pathological protein aggregates in Alzheimer's disease, particularly amyloid-beta plaques and tau tangles that disrupt synaptic transmission and neuronal survival. This hypothesis proposes that pharmacological or genetic activation of TFEB (Transcription Factor EB) can restore lysosomal biogenesis and autophagy flux specifically in Alzheimer's disease-affected brain regions. TFEB, a master regulator of the autophagy-lysosomal pathway, becomes sequestered in the cytoplasm during aging and neurodegeneration, reducing its nuclear translocation and transcriptional activity. By enhancing TFEB nuclear localization through mTORC1 inhibition, trehalose treatment, or direct TFEB overexpression, we can upregulate expression of lysosomal genes including LAMP1, cathepsins, and V-ATPase subunits. This enhanced lysosomal capacity will improve clearance of aggregated amyloid-beta oligomers and hyperphosphorylated tau from synaptic terminals and neuronal soma. The intervention is expected to be most effective in early-stage Alzheimer's disease before extensive neuronal loss occurs.
...Curated pathway from expert analysis
flowchart TD
A["mTORC1 Hyperactivation<br/>Nutrient/Growth Signals"]
B["TFEB Phosphorylation<br/>Ser211 by mTORC1"]
C["14-3-3 Sequestration<br/>Cytoplasmic Retention"]
D["Lysosomal Biogenesis<br/>Blocked"]
E["Autophagic Flux<br/>Impaired"]
F["Tau/Amyloid Aggregate<br/>Accumulation"]
G["TFEB Activation<br/>Rapamycin or MCOLN1"]
H["Nuclear TFEB<br/>CLEAR Gene Expression"]
G --> H
H -.->|"rescues"| D
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TFEB yet. Search RCSB →
Median TPM across 13 brain regions for TFEB 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 TFEB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF APP/PS1 transgenic mice at 4 months of age (early-stage AD) receive daily intraperitoneal trehalose (2% w/v in drinking water) for 12 weeks THEN cortical and hippocampal levels of soluble amyloid-b | 30% reduction in soluble cortical Aβ40 and Aβ42 concentrations and 50% increase in TFEB target gene expression after 12-week trehalose intervention | — no observation — | pending | 0.65 |
| IF 3xTg-AD mice at 6 months of age receive mTORC1 inhibitor rapamycin (10 mg/kg i.p., 3x/week) for 16 weeks THEN lysosomal enzyme activity in cortical tissue will increase by ≥40% measured by fluorome | 40% increase in lysosomal protease activity and 25% improvement in synaptic plasticity (LTP magnitude) following mTORC1 inhibition | — no observation — | pending | 0.55 |