ABCA7基因突变与阿尔茨海默病病理机制研究

Alzheimer's disease (AD) is the most common type of dementia, but effective treatments are lacking. Mutations in the ABCA7 gene are one of the risk factors for AD. Our previous research has shown that loss of ABCA7 function leads to abnormal phospholipid metabolism, which may alter the phospholipid composition of lysosomal membranes and inhibit lysosomal function. The byproduct of Aβ, βCTF, also exhibits neurotoxicity, leading to lysosomal acidification abnormalities, neuronal death, and subsequent Aβ release. Microglia can receive pathogenic proteins from neurons via tunneling nanotubes (TNTs), thereby alleviating neuronal stress. Additionally, TNTs can also transmit lysosomes. Therefore, we hypothesize that abnormally acidified lysosomes containing βCTF can be transferred to microglia via TNTs, and that loss of ABCA7 function alters phospholipid composition and ratios, inhibiting the lysosomal degradation of pathogenic proteins such as βCTF by microglia, thus promoting early pathological progression in AD. This study will use 5×FAD transgenic mouse models with ABCA7 mutations or knockouts, as well as primary cell co-culture systems, to investigate the effects and mechanisms of ABCA7 on the formation of microglia-neuron TNTs and the handling of abnormally acidified lysosomes, aiming to reveal new mechanisms of AD and explore therapeutic targets.