A prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood. Here, we report that 5xFAD mice, an animal model of AD, expressing signaling‐deficient variants of the p75 neurotrophin receptor (p75^NTR) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75^NTR knock‐in mice lacking the death domain or transmembrane Cys²⁵⁹ showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress, and neurite dystrophy than global knock‐outs. Strikingly, long‐term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock‐in mice. Mechanistically, we found that p75^NTR interacts with APP at the plasma membrane and regulates its internalization and intracellular trafficking in hippocampal neurons. Inactive p75^NTR variants internalized considerably slower than wild‐type p75^NTR and showed increased association with the recycling pathway, thereby reducing APP internalization and co‐localization with BACE1, the critical protease for generation of neurotoxic APP fragments, favoring non‐amyloidogenic APP cleavage. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing, and disease progression, and suggest that inhibitors targeting the p75^NTR transmembrane domain may be an effective therapeutic strategy in AD.

中文翻译：

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死亡受体 p75NTR 的失活变体通过干扰 APP 内化来减轻阿尔茨海默病的神经病理学


阿尔茨海默病 (AD) 发病机制的一个流行模型假设淀粉样前体蛋白 (APP) 内化到内吞区室后会产生神经毒性片段。调节 APP 内化和神经元细胞内运输的分子途径尚不完全清楚。在这里，我们报告说，5xFAD 小鼠（一种 AD 动物模型）表达 p75 神经营养蛋白受体 (p75 ^NTR ) 的信号传导缺陷变体，与缺乏该受体的动物相比，对 AD 神经病理学具有更强的神经保护作用。与整体敲除小鼠相比，缺乏死亡结构域或跨膜 Cys ²⁵⁹的 p75 ^NTR敲入小鼠表现出较低水平的 Aβ 种类、淀粉样斑块负荷、神经胶质增生、线粒体应激和神经突营养不良。引人注目的是，在 5xFAD 小鼠中完全破坏的长期突触可塑性和记忆在敲入小鼠中完全恢复。从机制上讲，我们发现 p75 ^NTR与质膜上的 APP 相互作用，并调节其在海马神经元中的内化和细胞内运输。无活性的 p75 ^NTR变体的内化速度比野生型 p75 ^NTR慢得多，并且与回收途径的关联性增强，从而减少了 APP 的内化以及与 BACE1 的共定位（BACE1 是生成神经毒性 APP 片段的关键蛋白酶），有利于非淀粉样蛋白形成的 APP 裂解。这些结果揭示了一种直接且特异性调节 APP 内化、淀粉样蛋白生成加工和疾病进展的新途径，并表明针对 p75 ^NTR跨膜结构域的抑制剂可能是 AD 的有效治疗策略。