Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Neuroscience, Morsani College of Medicine, University of South Florida, Tampa 33613, Florida, USA.
Nat Commun. 2012 Apr 10;3:777. 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.
在散发性与年龄相关的阿尔茨海默病（AD）中，淀粉样蛋白-β（Aβ）肽为何会积聚尚不清楚。在这里，我们表明可溶性淀粉样前体蛋白-α（sAPP-α）通过直接与β-位点 APP 转化酶（BACE）1 结合，从而调节 APP 加工，从而减少 Aβ 的生成。虽然使用抗体特异性靶向 sAPP-α会增强 Aβ 的产生；在具有 AD 样病理的转基因小鼠中，sAPP-α过表达会减少β-淀粉样斑块和可溶性 Aβ。支持这一观点的是，sAPP-α 的免疫中和会增加这些小鼠中 APP 淀粉样蛋白形成的处理。鉴于我们目前的发现，并且由于散发性 AD 的许多风险因素会降低 AD 患者大脑中的 sAPP-α 水平，因此 sAPP-α 水平不足可能足以使 APP 加工向淀粉样蛋白、Aβ 产生途径倾斜。因此，恢复 sAPP-α 或增强其与 BACE 的关联可能是改善导致 AD 发病机制的 APP 加工失衡的可行策略。
