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Mitochondrial Dynamics in Alzheimer’s Disease

Opportunities for Future Treatment Strategies

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Abstract

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.

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Acknowledgements

Work in the authors’ laboratories is supported by the National Institutes of Health (AG031852) and the Alzheimer’s Association (IIRG-07-60196). Mark Smith and Xiongwei Zhu have acted as consultants to and received honoraria from Pfizer and Medivation. The other authors have no conflicts of interest that are directly relevant to the content of this article.

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  1. Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio, 44106, USA

    David J. Bonda, Xinglong Wang, George Perry,  Mark A. Smith &  Xiongwei Zhu

  2. UTSA Neurosciences Institute and Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, Texas, USA

    George Perry

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  1. David J. Bonda
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  2. Xinglong Wang
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  3. George Perry
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Correspondence to Mark A. Smith or Xiongwei Zhu.

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Bonda, D.J., Wang, X., Perry, G. et al. Mitochondrial Dynamics in Alzheimer’s Disease. Drugs Aging 27, 181–192 (2010). https://doi.org/10.2165/11532140-000000000-00000

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