Selective autophagy inhibition alleviates oxidative stress-associated neurodegeneration in an AD+CCH model

Abstract

Dysregulated autophagy is increasingly implicated in the progression of Alzheimer's disease (AD), particularly when chronic cerebral hypoperfusion (CCH) coexists and exacerbates neurodegeneration. However, the relationship between autophagy dysregulation and oxidative stress responses under combined AD+CCH conditions remains incompletely understood. Here, APP/PS1 transgenic mice subjected to CCH were used to evaluate the effects of autophagy modulation with 3-methyladenine (3MA) and rapamycin (RAPA). CCH worsened cognitive impairment and neuronal injury in APP/PS1 mice and was accompanied by altered LC3-II and p62 expression, consistent with disturbed autophagy-related processing. These changes occurred together with increased expression of proteins associated with oxidative stress responses, including Keap1, Nrf2, HO-1, HIF-1α, and NOX-1. Notably, 3MA improved behavioral performance, reduced Aβ40 burden, and was associated with partial normalization of p62, Keap1, Nrf2, and downstream oxidative stress-related proteins. In contrast, RAPA did not confer detectable protection in this model. Age-stratified analyses further showed that abnormalities in autophagy- and oxidative stress-related markers were more severe at 12 months than at 9 months. Collectively, these findings support an association between altered autophagy-related processing and oxidative stress signaling in AD with chronic hypoperfusion and nominate the p62-Keap1-Nrf2 pathway as a candidate mechanism for further causal investigation.