PSMD4 Alleviates Aβ₁₋₄₂-Induced Mitochondrial Dysfunction and Oxidative Stress via the PGC-1α/Nrf Axis in Alzheimer's Disease Models.

This study aimed to investigate the role of 26S proteasome non-ATPase regulatory subunit 4 (PSMD4) in regulating mitochondrial function and oxidative stress in Alzheimer's disease (AD) and to explore its potential molecular mechanism in Aβ-induced neurotoxicity. An in vitro AD model was established by treating Neuro-2a cells with Aβ₁₋₄₂, and PSMD4 was overexpressed using a lentiviral vector. Flow cytometry was employed to assess reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm). Quantitative PCR and Western blotting were utilized to examine the expression of mitochondrial biogenesis-associated regulators, including PGC-1α, Nrf1, Nrf2, and TFAM. For the in vivo study, APP/PS1 double-transgenic mice served as the AD model. Histological analyses (HE and Nissl staining), immunofluorescence, and Western blotting were performed to evaluate hippocampal neuronal morphology and the expression of PSMD4 and mitochondrial marker TOM20. Aβ₁₋₄₂ significantly increased ROS levels, reduced ΔΨm, and downregulated the expression of PGC-1α, Nrf1, Nrf2, and TFAM in Neuro-2a cells. PSMD4 overexpression attenuated these changes, suggesting a protective role against mitochondrial dysfunction and oxidative stress. In APP/PS1 mice, hippocampal neurons showed morphological damage with reduced Nissl substance and decreased PSMD4 and TOM20 expression. Immunofluorescence revealed cytoplasmic PSMD4 localization and enhanced co-localization with MAP2, TOM20, and Aβ₁₋₄₂ in transgenic mice. PSMD4 is downregulated in AD models, and its overexpression ameliorates Aβ-induced oxidative stress and mitochondrial impairment, potentially by promoting mitochondrial biogenesis. These findings suggest that PSMD4 may serve as a novel therapeutic target for AD intervention.