• Open Access

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia

Authors

  • Robert Tamayev,

    1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
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    • These authors contributed equally to the work presented in this manuscript.

  • Shuji Matsuda,

    1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
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    • These authors contributed equally to the work presented in this manuscript.

  • Ottavio Arancio,

    1. Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA
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  • Luciano D'Adamio

    Corresponding author
    1. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
    2. Institute of Cellular Biology and Neurobiology, National Council of Research of Rome, Rome, Italy
    • Tel: +1 718 430 3244; Fax: +1 718 430 8711

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Abstract

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ.

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