P3‐459: Latrepirdine (Dimebon™) modulate mitochondrial dynamics in AD cell models

Genetic, biochemical, and cellular studies have implicated a fundamental involvement of mitochondria in Alzheimer disease (AD). Mitochondria are very dynamic organelles that continuously divide and fuse with each other. The delicate balance of mitochondrial fission and fusion controls not only mitochondrial morphology and number but also mitochondrial function and distribution, which is of paramount importance in neuronal function including synaptic function. Mitochondrial dysfunction and synaptic dysfunction are prominent early features in AD brain, and our recent studies suggest that an abnormal mitochondrial dynamic is involved in mitochondrial dysfunction and neuronal dysfunction including synaptic dysfunction and we propose that abnormal mitochondrial dynamics causes mitochondrial ultrastructural defects, dysfunction, and redistribution which adversely affects neuronal functions including causing synaptic abnormalities in AD. Dimebon is a very promising drug for the treatment of AD. However, its mechanisms of action are unclear. It is demonstrated that Dimebon modulates mitochondrial function in cells with nM potency and stabilizes mitochondria and improves neuron survival in the setting of cell stress, suggesting that mitochondria are a likely target of this promising drug. In this study, we explored the effects of Dimebon on mitochondrial dynamics in AD cell models (M17 neuroblastoma cells overexpressing wild type APP or mutant APP and primary hippocampal neurons treated with Abeta oligomers). By confocal and electron microscopy, various mitochondrial parameters including morphology, distribution, axonal transport and function were assessed in AD cell models treated with various concentration of Dimebon. We found that Dimebon induces changes in the expression of mitochondrial fission/fusion proteins and causes enhanced mitochondrial fission without apparent ultra-structural damage. It also enhances mitochondrial axonal transport in both anterograde and retrograde directions and affects mitochondrial density in neurites Moreover, Dimebon influences mitochondrial morphology and distribution in ADDL-treated neurons which correlates with synaptic alterations. We demonstrated that Dimebon modulates mitochondrial dynamics and it is likely that Dimebon-induced changes in mitochondrial dynamics contribute to its protective effect in AD.