Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques
Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques
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DOI：
10.1073/pnas.1510329112
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发表时间：
2015-07-14
影响因子：
11.1
通讯作者：
Ferguson, Shawn M.
中科院分区：
文献类型：
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作者：
Gowrishankar, Swetha;Yuan, Peng;Ferguson, Shawn M.
通过对阿尔茨海默病小鼠模型中细胞器标志物的全面分析，我们记录了淀粉样斑块中溶酶体样细胞器的大量积累，并确定这些细胞器中的大多数位于接触淀粉样沉积物的肿胀轴突内。从β-淀粉样蛋白沉积的最早阶段就观察到轴突溶酶体积累和细胞外淀粉样蛋白聚集体之间的这种密切的空间关系。值得注意的是，我们发现在这样的轴突中积累的溶酶体缺乏多种可溶性管腔蛋白酶，因此预测不能有效地降解蛋白质类货物。与阿尔茨海默病相关的是β-分泌酶（BACE 1），其是启动淀粉样前体蛋白的淀粉样蛋白形成加工的蛋白质，并且是这些蛋白酶的底物，在这些位点积聚。此外，通过在淀粉样蛋白斑块和野生型脑的神经元溶酶体的轴突溶酶体积累之间的比较，我们确定了一个类似的，自然发生的群体的溶酶体样细胞器在神经元的过程中，也被定义为其低管腔蛋白酶含量。结合新出现的证据，溶酶体成熟的内体和自噬体是耦合到他们的逆行运输，我们的研究结果表明，细胞外β-淀粉样蛋白沉积引起局部损伤的溶酶体前体的逆行轴突运输，导致其积累和封锁，在他们的进一步成熟。这项研究既促进了对阿尔茨海默病脑病理学的理解，又为神经元溶酶体的亚细胞组织提供了新的见解，这些亚细胞组织可能与其他神经退行性疾病具有更广泛的相关性，其中溶酶体组分与其病理学有关。
Through a comprehensive analysis of organellar markers in mouse models of Alzheimer's disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of beta-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer's disease, beta-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wildtype brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular beta-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer's disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.