Mitochondrial dynamics as a therapeutic target for Alzheimer disease

Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer′s disease which likely plays a critical role in the pathogenesis of disease. Mitochondria are dynamic organelles and the balance of mitochondrial fission and fusion determines Our initial studies revealed an imbalance in mitochondrial fission and fusion in fibroblasts from sporadic AD patients compared with normal healthy fibroblasts from age-matched control patients. Later it was demonstrated that overexpression of familial Alzheimer disease(FAD)-causing AβPP mutant or exposure to soluble Aβ oligomers led to mitochondrial fragmentation and redistribution in neuronal cells along with altered expression of mitochondrial fission/fusion proteins. Marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of AD mouse model CRND8 as early as three months of age before the accumulation of amyloid pathology. Importantly,we demonstrate significant changes in the expression and distribution of mitochondrial fission and fusion proteins in vivo in AD in consistent with a shifted mitochondrial dynamics towards excessive fission. Most recently,we demonstrated that genetic and pharmaceutical methods to rescue mitochondrial morphology and distribution could effectively restore Aβ-induced mitochondrial function and alleviate synaptic dysfunction both in vitro and in vivo,suggesting a causal involvement of mitochondrial dynamics in mediating Aβ-induced mitochondrial dysfunction. Taken together,we suggest that such a fundamental shift in mitochondrial dynamics negatively impacts all aspect of mitochondrial function such as impaired bioenergetics,increased structural damage and ROS production and loss of mt DNA integrity which causes synaptic dysfunction and neuronal dysfunction that is critical to AD pathogenesis. Therefore,strategies to modify abnormal mitochondrial dynamics may be an attractive therapeutic intervention target for AD.