Mitochondria Dynamics Abnormalities in Alzheimer Disease

Mitochondrial dysfunction has long been implicated in the pathogenesis of Alzheimer disease (AD). Mitochondrial function is highly dependent on mitochondria morphology dynamics, which are regulated by mitochondria fission/fusion proteins, i.e., DLP1/Fis1 for fission, and Mfn1/Mfn2/OPA1 for fusion. In this study, we found that levels of DLP1, OPA1, Mfn1 and Mfn2 were reduced while the level of Fis1 was increased in AD hippocampus. More importantly, all these proteins accumulated in the soma and depleted in neuronal processes in AD neurons. To explore the consequence of changes in these mitochondrial fission/fusion proteins, we manipulated the expression of them in M17 cells and primary hippocampal neurons in a way that mimicked their expression changes in AD and found that despite their differential effects on mitochondrial morphology, they all caused reduced mitochondrial density in cell periphery or neuronal processes. In an attempt to address the potential cause of abnormal mitochondrial dynamics, we found that ADDLs treatment not only led to mitochondrial fragmentation but also led to mitochondrial depletion from neuronal processes. Interestingly, the overexpression of DLP1 rescued ADDLs‐induced abnormal mitochondrial distribution while overexpression of OPA1 restored ADDLs‐induced mitochondrial fragmentation. Most importantly, we found ADDLs‐induced mitochondrial depletion correlated with reduced spine density and synaptophysin density and puncta number in neuronal processes, which could be effectively reversed by overexpression of DLP1 through repopulation of neuronal processes with mitochondria. Taken together, we suggest an impaired regulation of mitochondrial dynamics caused mitochondrial dysfunction and neuronal dysfunction in AD neurons.