Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits
Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits
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DOI：
10.1093/brain/awq341
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发表时间：
2011-01-01
期刊：
影响因子：
14.5
通讯作者：
Nixon, Ralph A.
中科院分区：
文献类型：
--
作者：
Yang, Dun-Sheng;Stavrides, Philip;Nixon, Ralph A.
自噬是蛋白质和细胞器的主要降解途径，对成熟神经元的存活至关重要。广泛的自噬-溶酶体病理在阿尔茨海默病的脑有助于阿尔茨海默病的发病机制，虽然其潜在的机制还没有得到很好的理解。在这里，我们确定并表征了阿尔茨海默病小鼠模型TgCRND 8中显著的神经元内淀粉样蛋白-β肽/淀粉样蛋白和溶酶体系统病理学，其与先前在阿尔茨海默病大脑中描述的相似。我们进一步确定，这些病理的基础涉及有缺陷的蛋白水解清除神经元自噬底物，包括淀粉样β肽。为了确定这些异常的致病意义，我们通过基因删除半胱氨酸蛋白酶抑制剂B（一种溶酶体半胱氨酸蛋白酶的内源性抑制剂）来增强TgCRND 8小鼠的溶酶体组织蛋白酶活性和自噬蛋白周转率。半胱氨酸蛋白酶抑制剂B缺失挽救了自噬-溶酶体病理学，减少了自溶酶体/溶酶体内淀粉样蛋白-β肽、泛素化蛋白和其他自噬底物的异常积累，并减少了神经元内淀粉样蛋白-β肽。TgCRND 8中溶酶体功能的改善显著降低细胞外淀粉样蛋白沉积和总脑淀粉样蛋白-β肽40和42水平，并防止恐惧条件反射和嗅觉习惯化测试中学习和记忆缺陷的发展。我们的研究结果支持自噬溶酶体功能障碍在阿尔茨海默病中的致病意义，并表明恢复正常自噬作为阿尔茨海默病的创新治疗策略的潜在价值。
Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-beta peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-beta peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-beta peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-beta peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-beta peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease.