Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease
Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease
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DOI：
10.1038/nn1630
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发表时间：
2006-02
影响因子：
25
通讯作者：
Lixia Zhao;Qiu-lan Ma;F. Calon;M. Harris-White;Fusheng Yang;G. Lim;T. Morihara;O. Ubeda;Surendra S. Ambegaokar;J. Hansen;R. Weisbart;B. Teter;S. Frautschy;G. Cole
中科院分区：
文献类型：
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作者：
Lixia Zhao;Qiu-lan Ma;F. Calon;M. Harris-White;Fusheng Yang;G. Lim;T. Morihara;O. Ubeda;Surendra S. Ambegaokar;J. Hansen;R. Weisbart;B. Teter;S. Frautschy;G. Cole
树突棘的缺陷是常见的几种形式的认知缺陷，包括精神发育迟滞和阿尔茨海默病。由于p21激活激酶（PAK）的突变可导致智力低下，因为PAK-cofilin信号转导在树突棘形态发生和肌动蛋白动力学中至关重要，我们假设PAK通路参与阿尔茨海默病的突触和认知缺陷。在这里，我们表明，阿尔茨海默病中PAK及其活性显着降低，并且这伴随着磷酸PAK的减少和重新分布、明显的丝切蛋白病理学以及脊柱肌动蛋白调节蛋白drebrin的下游丢失，丝切蛋白将其从肌动蛋白中去除。我们发现β-淀粉样蛋白（Aβ）直接参与了Aβ寡聚体处理的海马神经元和携带导致Aβ产生更高的双突变的Appswe转基因小鼠模型中PAK信号转导缺陷和神经元丢失。此外，成年小鼠中的药理学PAK抑制足以引起类似的cofilin病理学、记忆丧失和记忆障碍，这与PAK缺陷在阿尔茨海默病认知缺陷中的潜在因果作用一致。
Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that β-amyloid (Aβ) was directly involved in PAK signaling deficits and drebrin loss in Aβ oligomer–treated hippocampal neurons and in theAppswe transgenic mouse model bearing a double mutation leading to higher Aβ production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.