Soluble amyloid precursor protein-[alpha] modulates [beta]-secretase activity and amyloid-[beta] generation

• Published in: Nature communications 2012-04, Vol.3, p.777
• Main Authors: Obregon, Demian, Hou, Huayan, Deng, Juan, Giunta, Brian, Tian, Jun, Darlington, Donna, Shahaduzzaman, Md, Zhu, Yuyuan, Mori, Takashi, Mattson, Mark P, Tan, Jun
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Brain; Enzymes; Metabolism; Metabolites; Mutation; Neurosciences; Oxidative stress; Pathology; Peptides; Proteins; Risk factors; Transgenic animals
• ISSN: 2041-1723
• DOI: 10.1038/ncomms1781

In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-β (Aβ) peptides accumulate. Here we show that soluble amyloid precursor protein-α (sAPP-α) decreases Aβ generation by directly associating with β-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-α using antibodies enhances Aβ production; in transgenic mice with AD-like pathology, sAPP-α overexpression decreases β-amyloid plaques and soluble Aβ. In support, immunoneutralization of sAPP-α increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-α in brains of AD patients, inadequate sAPP-α levels may be sufficient to polarize APP processing towards the amyloidogenic, Aβ-producing route. Therefore, restoration of sAPP-α or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.