Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Article type: Research Article
Authors: Peters-Libeu, Clarea; * | Campagna, Jesusb | Mitsumori, Michaela | Poksay, Karen S.a | Spilman, Patriciab | Sabogal, Alexa | Bredesen, Dale E.a; b; c; 1 | John, Varghesea; b; c; 1; *
Affiliations: [a] Buck Institute for Research on Aging, Novato, CA, USA | [b] Drug Discovery Laboratory, Department of Neurology, UCLA, Los Angeles, CA, USA | [c] Easton Center for Alzheimer’s Disease Research, UCLA, Los Angeles, CA, USA
Correspondence: [*] Correspondence to: Varghese John, Easton Center for Alzheimer’s Disease Research, UCLA, Los Angeles, CA 90025, USA. Tel.: +1 310 206 4345; E-mail: [email protected]
Correspondence: [*] Correspondence to: Clare Peters-Libeu, Buck Institute for Research on Aging, Novato, CA 94945, USA. Tel.: +1 415 209 2000; [email protected]
Note: [1] These two authors share senior authorship.
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.
Keywords: Aβ, sAβPPα, sAβPPβ, allosteric, BACE, BACE1, endogenous, inhibitor, SAXS
DOI: 10.3233/JAD-150282
Journal: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 545-555, 2015
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
[email protected]
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]