Bim is elevated in Alzheimer's disease neurons and is required for β-amyloid-induced neuronal apoptosis
Bim is elevated in Alzheimer's disease neurons and is required for β-amyloid-induced neuronal apoptosis
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DOI：
10.1523/jneurosci.3524-06.2007
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发表时间：
2007-01-24
影响因子：
5.3
通讯作者：
Greene, Lloyd A.
中科院分区：
文献类型：
--
作者：
Biswas, Subhas C.;Shi, Yijie;Greene, Lloyd A.
介导阿尔茨海默病（AD）中神经元死亡的分子在很大程度上是未知的。我们报告，β-淀粉样蛋白（A β），一个死亡促进肽参与AD的病理生理学，诱导促凋亡蛋白Bcl-2相互作用介质的细胞死亡（Bim）在培养的海马和皮质神经元。我们进一步发现Bim是A β诱导的神经毒性的重要介质。我们的检查尸检AD人脑还揭示了上调的Bim脆弱的内嗅皮层神经元，但不是在小脑，一个地区通常不受AD。越来越多的证据将细胞周期相关蛋白的不适当诱导/激活与AD联系起来，但它们在疾病中的作用尚不清楚。我们发现，细胞周期分子周期蛋白依赖性激酶4（cdk 4）和其下游效应B-myb，所需的A β依赖性Bim诱导和培养的神经元死亡。此外，在AD脑中过表达Bim的神经元也显示出细胞周期相关蛋白cdk 4和磷酸化Rb水平升高。我们的观察结果表明，Bim是一个促凋亡效应的A β和失调的细胞周期蛋白在AD和确定Bim和细胞周期元素作为潜在的治疗靶点。
The molecules that mediate neuron death in Alzheimer's disease (AD) are largely unknown. We report that beta-amyloid (A beta), a death-promoting peptide implicated in the pathophysiology of AD, induces the proapoptotic protein Bcl-2 interacting mediator of cell death (Bim) in cultured hippocampal and cortical neurons. We further find that Bim is an essential mediator of A beta-induced neurotoxicity. Our examination of postmortem AD human brains additionally reveals upregulation of Bim in vulnerable entorhinal cortical neurons, but not in cerebellum, a region usually unaffected by AD. Accumulating evidence links inappropriate induction/activation of cell cycle-related proteins to AD, but their roles in the disease have been unclear. We find that the cell cycle molecule cyclin-dependent kinase 4 (cdk4) and its downstream effector B-myb, are required for A beta-dependent Bim induction and death in cultured neurons. Moreover, neurons that overexpress Bim in AD brains also show elevated levels of the cell cycle-related proteins cdk4 and phospho-Rb. Our observations indicate that Bim is a proapoptotic effector of A beta and of dysregulated cell cycle proteins in AD and identify both Bim and cell cycle elements as potential therapeutic targets.