ALTERED BRAIN ENERGETICS INDUCES MITOCHONDRIAL FISSION ARREST IN ALZHEIMER’S DISEASE

Abstract

Mitochondrial dysfunction and altered cellular energetics are implicated in the etiology of Alzheimer's Disease (AD). Excessive mitochondrial division has been observed in cellular and animal models of familial AD (FAD), and in AD patients. Thus, understanding regional cellular responses to changes associated with disease progression, particularly regarding the relationship between mitochondrial energetics and the balance of mitochondrial fission and fusion, has the potential to elucidate basic mechanisms of disease while also suggesting targets of therapeutic opportunity Using three-dimensional reconstruction electron microscopy (3D EM) of brain tissue from AD patients and animal models of familial FAD, we elucidated changes in mitochondrial morphology in the context of three-dimensional architecture of the brain and mitochondria per se. We demonstrated that AD neuronal mitochondria display a highly exaggerated fission arrest phenotype that resembles “mitochondria-on-a-string” (MOAS) (Fig. 1b,c). MOAS formation was not associated with reduced levels of fission/fusion proteins or altered ability of Drp1 to translocate to mitochondria. The MOAS phenotype was mimicked in cultured neurons treated with the inhibitors of Drp1 GTPase activity and in mice under hypoxic conditions