Involvement of WAVE Accumulation in Aβ/APP Pathology-Dependent Tangle Modification in Alzheimer's Disease
Involvement of WAVE Accumulation in Aβ/APP Pathology-Dependent Tangle Modification in Alzheimer's Disease
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DOI：
10.2353/ajpath.2009.080908
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发表时间：
2009-07-01
影响因子：
6
通讯作者：
Shimohama, Shun
中科院分区：
文献类型：
--
作者：
Takata, Kazuyuki;Kitamura, Yoshihisa;Shimohama, Shun
突触缺陷与阿尔茨海默病（AD）的认知功能障碍密切相关，突触完整性受肌动蛋白细胞骨架的调节。我们在这里证明了Wiskott-Aldrich综合征蛋白家族verprolin同源蛋白（WAVE），肌动蛋白组装的关键分子，与过度磷酸化的tau蛋白和磷酸化的tau蛋白反应介导蛋白2（CRMP 2）在AD脑的神经元缠结和异常神经突中共聚集。尽管在JNPL 3小鼠的脑中诱导了磷酸化CRMP 2积累，但在分别发展神经元缠结和淀粉样蛋白-β（A β）斑块的JNPL 3或Tg 2576小鼠的脑中未检测到WAVE积累。有趣的是，磷酸化的CRMP 2积累和WAVE积累在产生神经元缠结和A β斑块的3xTg-AD小鼠的脑中重现。此外，我们发现AD脑的胞质部分中WAVE、CRMP 2和过度磷酸化的tau之间的相互作用。总之，WAVE积累可能需要A β/淀粉样前体蛋白和tau病理，并且WAVE、CRMP 2和过度磷酸化tau之间的相互作用可能参与该过程。因此，WAVE积累可能参与A β/淀粉样前体蛋白介导的缠结修饰，表明AD脑中肌动蛋白组装紊乱诱导的WAVE积累和突触缺陷之间可能存在相关性。(Am J Pathol 2009，175：17-24; DOI：10.2353/ajpath.2009.080908）
Synaptic deficits are closely correlated with cognitive dysfunction in Alzheimer's disease (AD), and synaptic integrity is regulated by the actin cytoskeleton. We demonstrated here that the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE), a key molecule for actin assembly, co-aggregated with both hyperphosphorylated tau and phosphorylated collapsin response mediator protein 2 (CRMP2) in neurofibrillary tangles and abnormal neurites of the AD brain. Although phosphorylated CRMP2 accumulation was induced in the brains of JNPL3 mice, WAVE accumulation was not detected in the brains of either JNPL3 or Tg2576 mice that developed neurofibrillary tangles and amyloid-beta (A beta) plaques, respectively. interestingly, both phosphorylated CRMP2 accumulation and WAVE accumulation were recapitulated in the brains of 3xTg-AD mice that developed neurofibrillary tangles and A beta plaques. in addition, we found an interaction between WAVE, CRMP2, and hyperphosphorylated tau in the cytosolic fraction of the AD brain. Taken together, WAVE accumulation may require both A beta/amyloid precursor protein and tau pathologies, and an interaction between WAVE, CRMP2, and hyperphosphorylated tau may be involved in this process. Thus, WAVE accumulation may be involved in A beta/amyloid precursor protein mediated-tangle modification, suggesting a possible correlation between WAVE accumulation and synaptic deficits induced by disturbances in actin assembly in AD brains. (Am J Pathol 2009, 175:17-24; DOI: 10.2353/ajpath.2009.080908)