NLRX1 orchestrates neuronal mitophagy in Alzheimer's Disease: a mechanistic exploration

Mitophagy dysfunction in Alzheimer's Disease (AD) accelerates disease progression, highlighting the need for novel therapeutic targets. Although Nucleotide oligomerization domain - like receptor X1 (NLRX1) regulates mitophagy, its role in AD remains unclear. This study aimed to elucidate NLRX1's function in AD - associated mitophagy and its therapeutic potential.

APP/PS1 transgenic mice and N2A - SW cells were used to establish AD models. Behavioral assays evaluated cognitive function in APP/PS1 mice, while transmission electron microscopy examined mitochondrial morphology. ELISA measured β - amyloid (Aβ)1-42 levels, and RT - qPCR and Western blot analyzed NLRX1 and mitophagy - related proteins after manipulating NLRX1 expression.

APP/PS1 mice had cognitive impairment, elevated Aβ1-42, and abnormal mitochondrial morphology, with reduced NLRX1 expression. NLRX1 - RNAi worsened mitochondrial function, increased Aβ1-42 and mitochondrial ROS, decreased the LC3B - II/I ratio, and upregulated Cyt - C, HSP60, and TIM23, while NLRX1 overexpression alleviated these effects. Co-immunoprecipitation confirmed NLRX1's interaction with key mitophagy protein.

NLRX1 is a key regulator of neuronal mitophagy in AD, and its downregulation impairs mitophagy, suggesting it as a potential therapeutic target.