The formation of amyloid-ß peptides (Aß), that accumulate in Alzheimer’s disease (AD) brains, involves proteolytic processing of the amyloid precursor protein (APP) firstly by ß-secretase (BACE1). Since BACE1 cleaves a plethora of other substrates, in this work we investigated whether the proteolysis and/or distribution of other BACE1 substrates, such as seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), is altered in AD. To test this we used 5xFAD mouse model brains that show an early accumulation of Aß plaques already at 2-months of age. Here we show for the first time that accumulation of BACE1 in peri-plaque regions and its enhanced levels in AD brains does not affect proteolysis of BACE1 substrates other than APP, such as Sez6 and Sez6L. We observed altered distribution of Sez6 and Sez6L in the area of Aß plaques in 5xFAD brains which is distinct to that of APP, BACE1 and/or LAMP1, suggesting different localization and/or function of these BACE1 substrates. While it is necessary to further elucidate the potential role that this may play in the course of AD, it is likely that Aß-targeted therapies may have beneficial effects against accumulation and/or altered distribution of BACE1 and its substrates, in addition to APP.

淀粉样蛋白-β 肽 (Aß) 在阿尔茨海默病 (AD) 大脑中积累，其形成首先涉及淀粉样蛋白前体蛋白 (APP) 通过 β-分泌酶 (BACE1) 进行蛋白水解加工。由于 BACE1 裂解大量其他底物，因此在这项工作中，我们研究了其他 BACE1 底物（例如癫痫蛋白 6 (Sez6) 和癫痫 6 样蛋白 (Sez6L)）的蛋白水解和/或分布在 AD 中是否发生改变。为了测试这一点，我们使用了 5xFAD 小鼠模型大脑，该模型显示 Aß 斑块在 2 个月大时就已早期积累。在这里，我们首次证明 BACE1 在斑块周围区域的积累及其在 AD 大脑中的增强水平不会影响除 APP 之外的 BACE1 底物（例如 Sez6 和 Sez6L）的蛋白水解。我们观察到 Sez6 和 Sez6L 在 5xFAD 大脑 Aß 斑块区域中的分布发生变化，这与 APP、BACE1 和/或 LAMP1 的分布不同，表明这些 BACE1 底物的定位和/或功能不同。虽然有必要进一步阐明这在 AD 过程中可能发挥的潜在作用，但除 APP 之外，Aß 靶向疗法可能对 BACE1 及其底物的积累和/或分布改变产生有益的作用。