Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

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Acknowledgments

This work was supported by grants from Synapsis Foundation, Novartis Foundation for Biomedical Research Basel and the Swiss National Science Foundation (#31003A_149728) to AE.

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Correspondence to Anne Eckert.

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Grimm, A., Friedland, K. & Eckert, A. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer’s disease. Biogerontology 17, 281–296 (2016). https://doi.org/10.1007/s10522-015-9618-4

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Keywords

  • Alzheimer’s disease
  • Brain aging
  • Mitochondrial dysfunction
  • Oxidative stress