Neuritic plaques in Alzheimer’s disease (AD) brains refer to β-amyloid (Aβ) plaques surrounded by dystrophic neurites (DNs), activated microglia and reactive astrocytes. Most recently, we showed that DNs form sequentially in three layers during plaque growth. Although lysosomal proteins such as LAMP1 are found in DNs, it is not clear how many and how early lysosomal proteins are involved in forming neuritic plaques. To answer this unmet question, we examined APP knock-in (APPNL-G-F), 5xFAD and APP/PS1ΔE9 mouse brains and found that the lysosomal activator proteins saposins (SAPs) and LAMP1 were accumulated to surround Aβ plaques at the earliest stage, namely the 1st layer of DNs. Noticeably, lysosomal hydrolases were not detectable in these early DNs, suggesting that DNs at this early stage likely enrich dysfunctional lysosomes. In old AD mouse brains and in the later stage of human AD brains, SAP-C+-DNs and LAMP1+-DNs were gradually reduced in concomitant with the growth of amyloid plaques. Remarkably, the observed LAMP1 immunoreactivity near plaques in aged AD mouse and human brains were actually associated with disease-associated microglia rather than neuronal sources, likely reflecting more severely impaired lysosomal functions in neurons. Western blot analyses showed increased levels of SAP-C in AD mouse brains, and Aβ oligomers induced elevated levels of SAP-C in cellular assays. The elevated protein levels of SAP-C in AD mouse brains during plaque growth potentially contributed lysosomal membrane leakage and loss of hydrolases. Together, our study indicates that lysosomal functions are impaired by being entrapped in DNs early during plaque growth, and this may viciously facilitate growth of amyloid plaques.

中文翻译：

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营养不良的神经突中皂苷的积累与阿尔茨海默病大脑中溶酶体功能受损有关

阿尔茨海默病 (AD) 大脑中的神经炎斑块是指被营养不良的神经突 (DN)、活化的小胶质细胞和反应性星形胶质细胞包围的 β-淀粉样蛋白 (Aβ) 斑块。最近，我们发现 DN 在斑块生长过程中按三层顺序形成。尽管在 DN 中发现了 LAMP1 等溶酶体蛋白，但尚不清楚有多少溶酶体蛋白以及如何早期参与神经炎斑块的形成。为了回答这个未解决的问题，我们检查了 APP 敲入 (APPNL-GF)、5xFAD 和 APP/PS1ΔE9 小鼠大脑，发现溶酶体激活蛋白 saposins (SAP) 和 LAMP1 在最早阶段就积累在 Aβ 斑块周围，即第一层 DN。值得注意的是，在这些早期 DN 中未检测到溶酶体水解酶，这表明早期阶段的 DN 可能会富集功能失调的溶酶体。在老年AD小鼠大脑和人类AD后期大脑中，SAP-C+-DN和LAMP1+-DN随着淀粉样斑块的生长而逐渐减少。值得注意的是，在老年 AD 小鼠和人脑斑块附近观察到的 LAMP1 免疫反应性实际上与疾病相关的小胶质细胞而不是神经元来源相关，这可能反映了神经元中溶酶体功能更严重受损。蛋白质印迹分析显示 AD 小鼠大脑中 SAP-C 水平升高，并且 Aβ 寡聚物在细胞检测中诱导 SAP-C 水平升高。在斑块生长过程中，AD 小鼠大脑中 SAP-C 蛋白水平升高，可能导致溶酶体膜渗漏和水解酶损失。总之，我们的研究表明，在斑块生长早期，溶酶体功能因被 DN 捕获而受损，这可能会恶性促进淀粉样斑块的生长。