Autophagy in aging and Alzheimer's disease: pathologic or protective?
Autophagy in aging and Alzheimer's disease: pathologic or protective?
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DOI：
10.3233/jad-2011-101989
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Brewer GJ
中科院分区：
文献类型：
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作者：
Barnett A;Brewer GJ
一些人假设，人类的衰老是大分子和线粒体损伤的累积过程，早在任何症状出现之前的几年甚至几十年就开始了。当损坏率超过持续修复和周转率时，老化就可能开始。对受损线粒体的质量控制需要通过线粒体自噬（一种特殊的自噬）进行细胞消化。保护性自噬不足可能会导致受损的细胞成分多年积累，直到影响细胞的正常功能。或者，衰老可能是过度活跃的病理性自噬的结果。目前的知识支持这两种假设，但数据相互矛盾，具体取决于检查自噬的哪个阶段。为了区分这些相反的假设，需要遵守两个标准。首先，是否存在可以通过刺激自噬清除的未消化废物的积累？其次，如果自噬过度活跃，抑制自噬是否可以挽救细胞、器官和生物体的死亡。这两者最好通过速率测量而不是单个时间点的测量来确定。在这里，我们回顾了自噬的一般过程，重点关注神经元线粒体自噬、衰老和阿尔茨海默氏病的有限信息。在两种小鼠模型中，雷帕霉素治疗消除了 AD 病理并逆转了记忆缺陷。作为一个工作模型，我们假设保护性自噬不足会加速衰老和阿尔茨海默病病理，这可能是由自噬体与溶酶体融合的缺陷引起的。
Some hypothesize that aging in humans is a cumulative process of macromolecular and mitochondrial damage starting years, even decades before any symptoms arise. Aging may begin when the rate of damage exceeds the rate of continual repair and turnover. Quality control for damaged mitochondria entails cellular digestion by mitophagy, a specialized kind of autophagy. Insufficient protective autophagy could cause damaged cellular components to accumulate over many years until they affect normal function in the cell. Alternatively, aging could be the result of overactive, pathologic autophagy. Current knowledge supports both hypotheses with conflicting data, depending on which stage of autophagy is examined. To distinguish these opposite hypotheses, two criteria need to be observed. First, is there a buildup of undigested waste that can be removed by stimulation of autophagy? Or second, if autophagy is overactive, does inhibition of autophagy rescue cell, organ and organism demise. Both of these are best determined by rate measures rather than measures at a single time point. Here, we review the generalized process of autophagy, with a focus on the limited information available for neuron mitophagy, aging and Alzheimer’s disease. In two mouse models, treatment with rapamycin abolishes the AD pathology and reverses memory deficits. As a working model, we hypothesize that insufficient protective autophagy accelerates both aging and Alzheimer’s disease pathology, possibly caused by defects in autophagosome fusion with lysosomes.