Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid beta accumulation, Tau hyperphosphorylation, and progressive neuronal injury. DJ-1 participates in regulating neuronal oxidative stress, mitochondrial function, and protein homeostasis, yet whether DJ-1 alleviates AD-like neuronal injury by regulating neurofilament light chain (NEFL) and autophagy remains unclear. This study investigated whether NEFL and autophagic homeostasis contribute to the neuroprotective effects of DJ-1 in AD-like neuronal injury. In aged mice, loss of DJ-1 led to learning and memory impairment, neuronal injury in the hippocampal CA3 region, abnormal APP abundance, and increased Tau phosphorylation, accompanied by decreased hippocampal NEFL expression and autophagic dysfunction. In contrast, DJ-1 overexpression improved AD-like pathological injury in APP/PS1 mice and HT-22 cells treated with Aβ25-35, restored NEFL expression, and alleviated autophagic dysfunction. Immunofluorescence showed overlapping spatial distributions of DJ-1 and NEFL in hippocampal neurons and HT-22 cells. Cycloheximide chase analysis further showed that DJ-1 overexpression slowed NEFL protein decay under Aβ25-35-induced injury. Notably, NEFL knockdown significantly weakened the ability of DJ-1 overexpression to improve AD-like pathological abnormalities and impaired autophagic flux. These findings suggest that NEFL contributes to DJ-1-mediated neuroprotection and autophagic flux regulation in AD-like neuronal injury. These results reveal a functional link among DJ-1, NEFL, and autophagic homeostasis and provide new evidence for understanding the mechanisms underlying DJ-1-mediated neuroprotection in AD-like injury.
