In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of β-amyloid (Aβ) peptide. Aβ deposition in turn causes accumulation of BACE1 in plaque-associated dystrophic neurites, thereby potentiating progressive Aβ deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE1 activity around plaques. The microtubule-associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aβ-induced transport deficits in vitro. In the current study, long-term in vivo two-photon microscopy and immunohistochemistry were performed in tau-deficient APPPS1 mice. Tau deletion reduced plaque-associated axonal pathology and BACE1 accumulation without affecting physiological BACE1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aβ deposition, presumably by contributing to accumulation of BACE1 in plaque-associated dystrophies. Targeting tau-dependent mechanisms could become a suitable strategy to specifically reduce overt BACE1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.

中文翻译：

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在阿尔茨海默氏病小鼠模型中，Tau缺失减少了斑块相关的BACE1积累，并降低了斑块形成。

在阿尔茨海默氏病中，BACE1蛋白酶启动淀粉样前体蛋白（APP）的淀粉样生成过程，最终导致β-淀粉样蛋白（Aβ）肽的合成。Aβ沉积反过来会导致BACE1在斑块相关的营养不良性神经突中积聚，从而一旦启动便增强了进行性Aβ沉积。由于全身性BACE抑制作用会对人体造成不良影响，因此重要的是确定能使斑块周围明显的BACE1活性正常化的策略。微管相关蛋白tau调节蛋白的轴突运输，而tau缺失可在体外挽救Aβ诱导的运输缺陷。在当前的研究中，在tau缺陷的APPPS1小鼠中进行了长期体内双光子显微镜和免疫组织化学。Tau删除减少斑块相关的轴突病理学和BACE1积累，而不会影响远离斑块的生理BACE1表达。因此，tau缺失有效地减缓了新斑块的形成并降低了斑块的致密性。数据显示，tau可能通过促进BACE1在斑块相关性营养不良中的积累而增强了Aβ的沉积。靶向tau依赖的机制可能成为一种合适的策略，以特异性地减少斑块周围明显的BACE1活性，从而避免全身性BACE抑制的不利影响。大概是由于在斑块相关的营养不良中促进了BACE1的积累。靶向tau依赖的机制可能成为一种合适的策略，以特异性地减少斑块周围明显的BACE1活性，从而避免全身性BACE抑制的不利影响。大概是由于在斑块相关的营养不良中促进了BACE1的积累。靶向tau依赖的机制可能成为一种合适的策略，以特异性地减少斑块周围明显的BACE1活性，从而避免全身性BACE抑制的不利影响。