Dasatinib plus Quercetin Senolytic Clearance of p16Ink4a-High Neurons in Alzheimer's and Parkinson's Disease Models
🧪 Overview
The dasatinib (D)+quercetin (Q) senolytic combination exploits differential dependencies on the Bcl-2 family anti-apoptotic network between senescent and non-senescent cells, with senescent neurons exhibiting elevated p16Ink4a expression and increased sensitivity to Bcl-2/Bcl-xL inhibition. D is a tyrosine kinase inhibitor that disrupts the AKT/FOXO3a survival pathway in senescent neurons, while Q is a natural flavonoid that inhibits PI3K/AKT signaling and suppresses HSP90-mediated stabilization of Bcl-2 family proteins. This hypothesis proposes that intermittent D+Q treatment (5 days on, 9 days off) selectively eliminates p16Ink4a-high senescent neurons in AD (APP/PS1) and PD (α-synuclein A53T) mouse models, reducing the SASP-driven neurotoxic milieu while preserving non-senescent neuronal populations. In AD models, senescent neurons accumulate in the entorhinal cortex and hippocampus, creating a non-cell-autonomous amplification loop through IL-6, IL-1β, and CXCL1 secretion that accelerates tau phosphorylation via GSK3β activation.
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["p16INK4a-High Senescent Neurons<br/>Entorhinal Cortex Hippocampus SN"]
B["Elevated BCL2 BCLxL Survival Shield<br/>Apoptosis Resistance"]
C["Dasatinib Inhibits AKT FOXO3a Pathway<br/>Survival Signal Disrupted"]
D["Quercetin Inhibits PI3K AKT<br/>HSP90-BCL2 Stabilization Suppressed"]
E["Synergistic Apoptosis Induction<br/>Selective Senescent Neuron Clearance"]
F["SASP Reduction IL-6 IL-1beta CXCL1<br/>Neurotoxic Milieu Cleared"]
G["GSK3beta tau Phosphorylation Decreased<br/>Synuclein Aggregation Reduced"]
H["Cognitive and Motor Function Improvement<br/>AD PD Neuroprotection"]
A --> B
B -.->|"resistance overcome by"| C
C --> E
D --> E
E --> F
F --> G
G --> H
style E fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CDKN2A
No curated PDB or AlphaFold mapping for CDKN2A yet. Search RCSB →
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 CDKN2A,BCL2,BCL2L1,FOXO3A,AKT1,PIK3CA,HSP90AA1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF 8-month-old APP/PS1 transgenic mice receive intermittent oral dasatinib (5mg/kg) plus quercetin (50mg/kg) treatment using a 5-days-on/9-days-off schedule for 3 cycles THEN cortical and hippocampal | p16Ink4a+ neuron density reduction >60%; Morris water maze performance improvement >40% relative to vehicle controls | — no observation — | pending | 0.45 |
| IF 10-month-old α-synuclein A53T transgenic mice receive the same intermittent dasatinib (5mg/kg) plus quercetin (50mg/kg) oral regimen (5 days on/9 days off, 3 cycles) THEN substantia nigra pars comp | TH+ neuron preservation >85%; rotarod performance improvement >35% relative to vehicle controls | — no observation — | pending | 0.40 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |