Mitochondrial Dynamics in Alzheimer’s Disease
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- Bonda, D.J., Wang, X., Perry, G. et al. Drugs Aging (2010) 27: 181. doi:10.2165/11532140-000000000-00000
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The complexities that underlie the cognitive impairment and neurodegeneration characteristic of Alzheimer’s disease (AD) have yet to be completely understood, although many factors in disease pathogenesis have been identified. Particularly important in disease development seem to be mitochondrial disturbances. As pivotal role players in cellular metabolism, mitochondria are pertinent to cell survival and thus any deviation from their operation is certainly fatal. In this review, we describe how the dynamic balance of mitochondrial fission and fusion in particular is a necessary aspect of cell proliferation and that, as the cell ages, such balance is inevitably compromised to yield a destructive environment in which the cell cannot exist. Evidence for such disturbance is abundant in AD. Specifically, the dynamic balance of fission and fusion in AD is greatly shifted toward fission, and, as a result, affected neurons contain abnormal mitochondria that are unable to meet the metabolic demands of the cell. Moreover, mitochondrial distribution in AD cells is perinuclear, with few metabolic organelles in the distal processes, where they are normally distributed in healthy cells and are needed for exocytosis, ion channel pumps, synaptic function and other activities. AD neurons are thus characterized by increases in reactive oxidative species and decreases in metabolic capability, and, notably, these changes are evident very early in AD progression. We therefore believe that oxidative stress and altered mitochondrial dynamics contribute to the precipitation of AD pathology and thus cognitive decline. These implications provide a window for therapeutic intervention (i.e. mitochondrial protection) that has the potential to significantly deter AD progression if adequately developed. Current treatment strategies under investigation are described in this review.