神经退行性变
内体
细胞生物学
拉布
淀粉样前体蛋白
星形胶质细胞
基因剔除小鼠
神经科学
细胞内
神经炎症
小胶质细胞
生物
GTP酶
阿尔茨海默病
内科学
医学
免疫学
生物化学
炎症
疾病
受体
中枢神经系统
作者
Meitian Wang,Xiuqing He,Jie Li,Daobin Han,Pan You,Hui Yu,Lu-Wen Wang,Bo Su
标识
DOI:10.1016/j.bbadis.2024.167093
摘要
Accumulation of insoluble deposits of amyloid β-peptide (Aβ), derived from amyloid precursor protein (APP) processing, represents one of the major pathological hallmarks of Alzheimer's disease (AD). Perturbations in APP transport and hydrolysis could lead to increased Aβ production. However, the precise mechanisms underlying APP transport remain elusive. The GDP dissociation inhibitor2 (GDI2), a crucial regulator of Rab GTPase activity and intracellular vesicle and membrane trafficking, was investigated for its impact on AD pathogenesis through neuron-specific knockout of GDI2 in 5xFAD mice. Notably, deficiency of GDI2 significantly ameliorated cognitive impairment, prevented neuronal loss in the subiculum and cortical layer V, reduced senile plaques as well as astrocyte activation in 5xFAD mice. Conversely, increased activated microglia and phagocytosis were observed in GDI2 ko mice. Further investigation revealed that GDI2 knockout led to more APP co-localized with the ER rather than the Golgi apparatus and endosomes in SH-SY5Y cells, resulting in decreased Aβ production. Collectively, these findings suggest that GDI2 may regulate Aβ production by modulating APP intracellular transport and localization dynamics. In summary, our study identifies GDI2 as a pivotal regulator governing APP transport and process implicated in AD pathology; thus highlighting its potential as an attractive pharmacological target for future drug development against AD.
科研通智能强力驱动
Strongly Powered by AbleSci AI