期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：E3699-E3708
DOI：10.1073/pnas.1510329112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAmyloid plaques, a key feature of Alzheimer's disease brain pathology, comprise an extracellular {beta}-amyloid core surrounded by tissue enriched in lysosome-like organelles. As a foundation for understanding the mechanisms that drive amyloid plaque formation, we have elucidated the cellular origins and molecular composition of such organelles. The majority of the lysosomes at amyloid plaques reside within swollen neuronal axons. Interestingly, these organelles contain low levels of multiple luminal lysosomal proteases and closely resemble a lysosome subpopulation that naturally occurs in distal neuronal processes. These results suggest that extracellular {beta}-amyloid deposits cause a local impairment in retrograde axonal transport, leading to the accumulation of lysosome precursors and a blockade in their further maturation that has implications for both {beta}-amyloid production and clearance. 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 wild-type 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.
关键词：lysosome ; Alzheimer's ; progranulin ; axonal transport ; cathepsin
