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sAβPPα is a Potent Endogenous Inhibitor of BACE1

Peters-Libeu, Clare, Campagna, Jesus, Mitsumori, Michael, Poksay, Karen S., Spilman, Patricia, Sabogal, Alex, Bredesen, Dale E., John, Varghese·2015·Journal of Alzheimer's Disease
DOI 10.3233/jad-150282
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Abstract

Proteolytic cleavage of the amyloid-β protein precursor (AβPP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-β peptide (Aβ), and as such has been a major target of Alzheimer's disease (AD) drug discovery efforts. Overproduction of Aβ results in neuronal cell death and accumulation of amyloid plaques in AD and in traumatic brain injury, and is also associated with stroke due to cerebral amyloid angiopathy. Herein we report for the first time that sAβPPα, the product of the cleavage of AβPP by α-secretase, is a potent endogenous direct inhibitor of the BACE enzyme, and that its inhibition is likely by an allosteric mechanism. Furthermore, using small-angle X-ray scattering, we show that sAβPPβ, which is identical to sAβPPα except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sAβPPα and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sAβPPα in regulating overproduction of Aβ and restoring neuronal homeostasis and neuroprotection. Identification of sAβPPα as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of Aβ.

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  • sAPPβ fails to interact with BACE-1 because the 16-amino-acid truncation at the carboxy end imposes significant structural changes compared with sAPPα.

    “sAPPβ, which fails to interact with BACE-1 because the truncation of 16 aminoacids at the carboxy end (sequence between the α- and β-cleavage sites) is sufficient to impose significant structural changes compared to sAPPα”

    From Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP (2019) · cites this paper as Peters-Libeu et al., 2015

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Metadata

Authors
Peters-Libeu, C., Campagna, J., Mitsumori, M., Poksay, K. S., Spilman, P., Sabogal, A., Bredesen, D. E., & John, V.
Affiliations
  • Buck Institute for Research on Aging, Novato, CA, USA
  • Drug Discovery Laboratory, Department of Neurology, UCLA, Los Angeles, CA, USA
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2015-08-03
Volume
47
Issue
3
Pages
545-555
ISSN
  • 1387-2877
  • 1875-8908
DOI
10.3233/jad-150282
Cited by
58
References
2

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