Impaired Balance of Mitochondria Fission and Fusion in Alzheimer Disease

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in selective brain regions. Mitochondrial dysfunction is a prominent and early feature of the disease, although the reason for this is unclear. Nonetheless, emerging evidence suggest that mitochondrial function is dependent on the dynamic balance of fission and fusion events which are regulated by mitochondria fission and fusion proteins (i.e. DLP1/OPA1/Mfn1/Mfn2/Fis1). While an impaired balance of mitochondria fission and fusion is being increasingly implicated in neurodegenerative diseases, few studies have examined this aspect in AD. To address this issue, in this study, we investigated mitochondria morphology and distribution in primary fibroblasts and neurons from normal subjects and those from AD patients. We found disease-related changes in mitochondrial morphology and distribution as well as changes in expression levels and distribution of mitochondrial fission and fusion proteins. To understand the underlying mechanisms of these mitochondria alterations in AD, we overexpressed or knocked down functional mitochondrial fission and fusion proteins in primary human fibroblasts, M17 cells (derived from a human neuroblastoma) and rat E18 primary hippocampal neurons. Interestingly, functional protein changes in AD fibroblasts or neurons mimicking that found in AD, are correlated with similar changes in mitochondrial morphology and distribution to that observed in AD fibroblasts or neurons. We further demonstrated that ROS or amyloid-β are likely the potential pathogenic factor that causes an impaired balance of mitochondrial fission/fusion, mitochondria dysfunction and even synaptic abnormalities. Taken together, this is the first study to show that ROS or amyloid-β might induce mitochondria dynamic abnormalities in mitochondria, mitochondrial dysfunction and further neuronal dysfunction through their different effect on mitochondrial fission and fusion proteins.