Peters-Libeu Clare, Campagna Jesus, Mitsumori Michael, Poksay Karen S, Spilman Patricia, Sabogal Alex, Bredesen Dale E, John Varghese
Buck Institute for Research on Aging, Novato, CA, USA.
Drug Discovery Laboratory, Department of Neurology, UCLA, Los Angeles, CA, USA.
J Alzheimers Dis. 2015;47(3):545-55. doi: 10.3233/JAD-150282.
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.
β-淀粉样蛋白前体（AβPP）被β-位点淀粉样前体蛋白裂解酶1（BACE1，简称BACE）进行蛋白水解切割是生成β-淀粉样肽（Aβ）的起始步骤，因此一直是阿尔茨海默病（AD）药物研发工作的主要靶点。Aβ过量生成会导致AD和创伤性脑损伤中神经元细胞死亡及淀粉样斑块积累，还与脑淀粉样血管病所致的中风有关。在此我们首次报道，α-分泌酶切割AβPP产生的产物sAβPPα是BACE酶的一种强效内源性直接抑制剂，其抑制作用可能通过变构机制实现。此外，利用小角X射线散射技术，我们发现sAβPPβ除了羧基末端有一个16个氨基酸的截短外与sAβPPα相同，但其结构与sAβPPα完全不同，且不抑制BACE。我们的数据因此揭示了sAβPPα在调节Aβ过量生成以及恢复神经元内环境稳定和神经保护方面发挥的一种新的机制性作用。将sAβPPα鉴定为直接的BACE抑制剂可能会引领针对与Aβ过量生成相关病症的新疗法设计。
