ATOX1 deficiency induces memory impairment via promoting cuproptosis in Alzheimer’s disease

Introduction Copper homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess copper exacerbates oxidative damage, protein aggregation and cognitive deficits. Cuproptosis is a new form of cell death mainly related to mitochondrial impairment which caused by intracellular copper overload. However, the involvement of cuproptosis in the pathogenesis of AD remains elusive. Objectives The copper chaperone ATOX1 is crucial for copper homeostasis. This study aimed to investigate the role of ATOX1 and cuproptosis in the progression of Alzheimer’s disease and to identify the underlying regulatory mechanism. Methods We analyzed human AD brain databases and tissue, alongside APP/PS1 mouse models and Aβ-treated HT22 cells. Techniques included proteomics, immunofluorescence, Western blot, electron microscopy, and behavioral tests. ATOX1 was manipulated using AAV vectors and shRNA in vivo and in vitro. Chromatin immunoprecipitation (ChIP) and luciferase assays were used to study transcriptional regulation. Results ATOX1 was significantly decreased in human AD brains, APP/PS1 mice, and Aβ-treated cells. ATOX1 downregulation in mice induced copper accumulation, mitochondrial damage, and molecular features of cuproptosis, including lipoylated protein aggregation and Fe-S cluster protein loss, leading to neuronal death and memory impairment. These cuproptosis markers were also confirmed in human AD brains and APP/PS1 mice. Critically, ATOX1 up-regulation reversed cuproptosis, ameliorated synaptic deficits, and rescued memory impairments in APP/PS1 mice and Aβ-treated cells. Furthermore, we identify Runx1 as a transcriptional repressor of ATOX1 under Aβ exposure, revealing a novel mechanism that couples amyloid pathology directly to copper dysregulation. Conclusion Our findings demonstrate that Aβ-induced Runx1 repression of ATOX1 drives copper overload and cuproptosis, contributing to neurodegeneration and cognitive deficits in AD. ATOX1 represents a promising therapeutic target for AD.