Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation

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