期刊
AUTOPHAGY
卷 7, 期 7, 页码 788-789出版社
LANDES BIOSCIENCE
DOI: 10.4161/auto.7.7.15596
关键词
autophagy; lysosome; cathepsin; cystatin B; proteolysis; Alzheimer disease; transgenic
类别
资金
- NIA NIH HHS [P01 AG017617, R01 AG037693] Funding Source: Medline
- Wellcome Trust [081864] Funding Source: Medline
The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neuro-degenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-beta peptide (A beta) accumulation, extracellular beta-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared A beta, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total A beta 40/42 levels and extracellular amyloid deposition, highlighting the under-appreciated importance of the lysosomal system for A beta clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeutic strategy for AD.
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