P3‐422: Impaired balance of mitochondrial fission and fusion in susceptible neurons of Alzheimer disease

Mitochondrial dysfunction is a prominent and early feature of Alzheimer disease (AD), although the underlying mechanisms remain elusive. Nonetheless, emerging evidence suggest that mitochondrial function is dependent on the dynamic balance of fission and fusion events which are regulated by a machinery involving large dynamin-related GTPases that exert opposing effects. While an impaired balance of mitochondria fission and fusion is being increasingly implicated in various neurodegenerative diseases, few studies have examined this aspect in AD. To address this issue, we investigated mitochondria morphology and distribution in biopsy brains from normal subjects and those from AD patients. The levels of fission and fusion in human brain were analyzed using immunoblot analysis. Additionally, these proteins were overexpressed or knocked-down in rat primary neurons. We found that mitochondria were redistributed away from axons and became more heterogeneous in AD neurons as evidenced by both confocal and electron microscopy studies. Immunoblot analysis revealed that levels of DLP1, OPA1, and Mfn1/2 were significantly decreased while levels of Fis1 were significantly increased in AD. Interestingly, all these proteins appeared to accumulate in the soma but not in the processes of pyramidal neurons in AD hippocampus in contrast to the even distribution in the cytoplasm and processes of pyramidal neurons in age-matched control hippocampus. We then overexpressed or knocked down functional mitochondrial fission/fusion proteins in rat primary neurons. Remarkably, in situations where functional protein changes mimicking that in AD, we found similar changes in mitochondrial distribution to that observed in vivo in AD neurons. We further demonstrated that elevated oxidative stress and increased amyloid-beta production are likely the potential pathogenic factors that cause this impaired balance of mitochondrial fission/fusion. AD brains demonstrate mitochondrial distribution and morphological abnormalities compared to age-matched controls. Levels of mitochondria fission/fusion proteins are changed in AD autopsy brains. Manipulation of mitochondria fission/fusion proteins mimicking that in AD causes similar mitochondrial abnormalities in rat primary neurons. ADDLs causes DLP1 downregulation and mitochondria abnomalities in mitochondria in primary neurons. Work in the authors' laboratories is supported by the National Institutes of Health (AG024028) and Alzheimer's Association (IIRG-07–60196).