Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. Synaptic dysfunction has appeared in the early stage of AD and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here we found upregulated Maf1 transcription factor in AD, and Maf1 conditional knockout in AD transgenic mice restored learning and memory function. Downregulation of Maf1 reduced intraneuronal Ca2+ concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulates the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodeling in neurons. Therefore, our results clarified the important role and mechanism of the Maf1-NMDAR1 signaling pathway in the stability of the synaptic structure, neuronal function, and behavior during the pathogenesis of AD, serving as a potential diagnostic and therapeutic target for the early onset of AD.
Keywords: Alzheimer's disease; MNDAR1; Maf1; calcium homeostasis; synaptic plasticity.
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.