Dasatinib plus Quercetin Senolytic Clearance of p16Ink4a-High Neurons in Alzhei…

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. In PD models, senescent dopaminergic neurons in the substantia nigra pars compacta exhibit increased α-synuclein aggregation, creating a bidirectional reinforcement between senescence and protein aggregation. The prediction is that D+Q treatment at 5mg/kg D and 50mg/kg Q (oral, 3 cycles) will reduce cortical and hippocampal p16Ink4a+ neuron density by >60%, decrease SASP cytokine levels (IL-6, TNF-α) in CSF, and improve Morris water maze performance in APP/PS1 mice by >40% compared to vehicle-treated controls. Critically, the intermittent dosing schedule minimizes off-target effects and allows immune-mediated clearance of apoptotic debris without inducing the cytokine storm associated with acute senolytic dosing. This approach represents a targeted application of the D+Q senolytic paradigm that has shown promise in aging studies, specifically adapted for the neuronal context and AD/PD therapeutic contexts.