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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