Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease

Authors

  • Norman J. Haughey,

    1. *Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
      Departments of †Neurology and ‡Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
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  • Avi Nath,

    1. *Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
      Departments of †Neurology and ‡Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
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  • Sic L. Chan,

    1. *Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
      Departments of †Neurology and ‡Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
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  • A. C. Borchard,

    1. *Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
      Departments of †Neurology and ‡Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
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  • Mahendra S. Rao,

    1. *Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
      Departments of †Neurology and ‡Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
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  • Mark P. Mattson

    1. *Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland, USA
      Departments of †Neurology and ‡Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
      §Department of Neurology, University of Kentucky, Lexington, Kentucky, USA
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Address correspondence and reprint requests to Mark P. Mattson, NIA Gerontology Research Center, 4F02, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. E-mail: mattsonm@grc.nia.nih.gov

Abstract

Neurogenesis occurs in the adult mammalian brain and may play roles in learning and memory processes and recovery from injury, suggesting that abnormalities in neural progenitor cells (NPC) might contribute to the pathogenesis of disorders of learning and memory in humans. The objectives of this study were to determine whether NPC proliferation, survival and neuronal differentiation are impaired in a transgenic mouse model of Alzheimer's disease (AD), and to determine the effects of the pathogenic form of amyloid β-peptide (Aβ) on the survival and neuronal differentiation of cultured NPC. The proliferation and survival of NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a mutated form of amyloid precursor protein that causes early onset familial AD. Aβ impaired the proliferation and neuronal differentiation of cultured human and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism involving dysregulation of cellular calcium homeostasis and the activation of calpains and caspases. Adverse effects of Aβ on NPC may contribute to the depletion of neurons and cognitive impairment in AD.

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