Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease
Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.162228299
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发表时间：
2002-08-06
影响因子：
11.1
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
DeMattos, RB;O'dell, MA;Holtzman, DM
研究表明，丛生蛋白（也称为载脂蛋白J）可以影响淀粉样蛋白β（Abeta）的结构和毒性。为了确定内源性clusterin是否在体内影响Abeta沉积、结构和毒性中起作用，我们将PDAPP小鼠（阿尔茨海默病的转基因小鼠模型）与clusterin（-/-）小鼠交配。到12月龄时，PDAPP，clusterin（-/-）小鼠具有与PDAPP，clusterin（+/+）小鼠相似的脑Abeta沉积水平。尽管Abeta沉积相似，但PDAPP，丛生蛋白（-/-）小鼠的纤维状Abeta（淀粉样蛋白）沉积物比表达丛生蛋白的PDAPP小鼠显著更少。在没有丛生蛋白的情况下，与淀粉样蛋白沉积相关的神经炎性营养不良显著减少，导致纤维状淀粉样蛋白形成和神经炎性营养不良之间的分离。这些结果表明，clusterin显着影响体内的A β结构和神经毒性，并可能在阿尔茨海默病的发病机制中发挥重要作用。
Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-beta (Abeta) in vitro. To determine whether endogenous clusterin plays a role in influencing Abeta deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Abeta deposition as did PDAPP, clusterin(+/+) mice. Although Abeta deposition was similar, PDAPP, clusterin(-/-) mice had significantly fewer fibrillar Abeta (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Abeta structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.