Reexamining Alzheimer's Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid-β
Reexamining Alzheimer's Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid-β
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DOI：
10.3233/jad-2009-1151
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发表时间：
2009-01-01
影响因子：
4
通讯作者：
Smith, Mark A.
中科院分区：
文献类型：
--
作者：
Castellani, Rudy J.;Lee, Hyoung-gon;Smith, Mark A.
阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的神经退行性疾病，其临床特征是认知能力下降，病理特征是含有淀粉样蛋白β的老年斑和神经纤维缠结的积累。大量的注意力集中在淀粉样蛋白-β作为主要的致病机制，最终目标是使用淀粉样蛋白-β降低疗法作为治疗途径。不幸的是，近四分之一世纪过去了，没有取得任何切实的进展，而最引人注目的往往是令人震惊的失败。我们长期以来一直认为，正如大量文献所述，蛋白质积聚只是疾病的下游，通常是疾病的终末期表现。他们与痴呆症水平的整体相关性很差，他们在认知上的存在是经常被忽视的证据，这是一个不方便的事实。因此，目前研究淀粉样蛋白寡聚体的研究将增加大量的细节，从本质上讲，这是一种还原主义者对上游多效性过程（如氧化应激、细胞周期功能障碍和炎症）的分心。神经科学家早就应该避免在“蛋白质病”上坚持下去的陷阱，并认识到在反复失败或更糟的情况下继续靶向终末期病变是一个失败的主张。
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused on amyloid-beta as the major pathogenic mechanisms with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies" and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.