sAβPPα is a Potent Endogenous Inhibitor of BACE1

Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) by the enzyme BACE1 (BACE) is the initial step in production of amyloid-beta peptide (A beta), and as such has been a major target of Alzheimer's disease (AD) drug discovery efforts. Overproduction of A beta 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 sA beta PP alpha, the product of the cleavage of A beta PP by alpha-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 sA beta PP beta, which is identical to sA beta PP alpha except for a 16-amino acid truncation at the carboxy terminus, adopts a completely different structure than sA beta PP alpha and does not inhibit BACE. Our data thus reveal a novel mechanistic role played by sA beta PP alpha in regulating overproduction of A beta and restoring neuronal homeostasis and neuroprotection. Identification of sA beta PP alpha as a direct BACE inhibitor may lead to design of new therapeutics targeting pathologies associated with overproduction of A beta.