Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline.
Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline.
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DOI：
10.1523/jneurosci.0490-10.2010
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发表时间：
2010-05-26
期刊：
影响因子：
--
通讯作者：
LaFerla FM
中科院分区：
文献类型：
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作者：
Clinton LK;Blurton-Jones M;Myczek K;Trojanowski JQ;LaFerla FM
阿尔茨海默病（Alzheimer's disease，AD）是最常见的年龄相关性神经退行性疾病，其病理学特征是β-淀粉样蛋白（Aβ）斑块和富含tau蛋白的神经元缠结的积累。有趣的是，高达50%的AD病例表现出第三种普遍的神经病理学：α-突触核蛋白聚集成路易体。重要的是，AD中路易体病理学的存在与更具侵袭性的病程和加速的认知功能障碍相关。因此，Aβ、tau和α-突触核蛋白可能协同相互作用以促进彼此的积累。在这项研究中，我们使用遗传方法来生成一个模型，该模型表现出AD和路易体痴呆（DLB）的综合病理。为了实现这一目标，我们将突变的人α-突触核蛋白转基因导入3xTg-AD小鼠。与人类疾病中发生的情况一样，发生DLB和AD病理的转基因小鼠（DLB-AD小鼠）表现出与Aβ、tau和α-突触核蛋白病理显著增强相关的加速认知衰退。我们的研究结果还提供了额外的证据，表明α-突触核蛋白的积累单独可以显着破坏认知。总之，我们的数据支持Aβ、tau和α-突触核蛋白在体内相互作用以促进彼此的聚集和积累并加速认知功能障碍的观点。
Alzheimer’s disease (AD), the most prevalent age-related neurodegenerative disorder, is characterized pathologically by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Interestingly, up to 50% of AD cases exhibit a third prevalent neuropathology: the aggregation of α-synuclein into Lewy bodies. Importantly, the presence of Lewy body pathology in AD is associated with a more aggressive disease course and accelerated cognitive dysfunction. Thus, Aβ, tau, and α-synuclein may interact synergistically to promote the accumulation of each other. In this study, we used a genetic approach to generate a model that exhibits the combined pathologies of AD and dementia with Lewy bodies (DLB). To achieve this goal, we introduced a mutant human α-synuclein transgene into 3xTg-AD mice. As occurs in human disease, transgenic mice that develop both DLB and AD pathologies (DLB-AD mice) exhibit accelerated cognitive decline associated with a dramatic enhancement of Aβ, tau, and α-synuclein pathologies. Our findings also provide additional evidence that the accumulation of α-synuclein alone can significantly disrupt cognition. Together, our data support the notion that Aβ, tau, and α-synuclein interact in vivo to promote the aggregation and accumulation of each other and accelerate cognitive dysfunction.