Development of trans-cellular propagation of tau by bimolecular fluorescence complementation technique

摘要

Mitochondrial dysfunction is a hallmark of Alzheimer’s disease (AD). Accumulating evidence suggests that clearance of damaged mitochondria, termed mitophagy, is dysregulated, thereby leading to the accumulation of damaged mitochondria in AD. Apolipopro- tein E (APOE) genotype is the strongest genetic risk factor for AD, with the ￠4 allele being an AD risk factor and the e2 allele being protective. APOE is a major lipoprotein in the brain which is primarily synthesized by astrocytes under normal conditions. Interestingly, ApoE is synthesized by neurons and undergoes frag- mentation under pathological conditions. Although neuronal ApoE is detected in mitochondria, it is not known whether neuronal ApoE affects mitophagy. To determine the effects of neuronal ApoE on mitophagy, we overexpressed ApoE isoforms in neuronal cells and assessed the effects of ApoE isoforms on mitophagy. Interest- ingly, the accumulation of PINK1 upon mitochondrial damage is significantly inhibited by ApoE4 compared to ApoE3, suggesting that ApoF4 prevents an induction of mitophagy. Our data indicate that ApoE4 may contribute to the pathogenesis of AD by impeding mitophagy. Further studies are warranted to determine the under- lying mechanisms of the effects of APOE genotype on mitophagy.