[Involvement of beta-amyloid in the etiology of Alzheimer's disease].
[Involvement of beta-amyloid in the etiology of Alzheimer's disease].
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发表时间：
2010-07
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通讯作者：
T. Tomiyama
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作者：
T. Tomiyama
淀粉样β-肽(Abeta)是阿尔茨海默病(AD)的关键分子。早些时候，脑内Abeta的沉积被认为启动了AD的病理性级联反应，包括老年斑和神经原纤维缠结的形成，神经元丢失和痴呆。根据经典的淀粉样蛋白假说，Abeta聚集成不溶性的β-折叠纤维在其神经毒性中起着重要作用。然而，这一假设是自相矛盾的：纤化和神经毒性所需的Abeta浓度高于其生理浓度。AD患者的认知功能减退与老年斑形成或不溶性Abeta的形成水平无关，而与突触丢失和可溶性Abeta的水平相关。这些观察表明，AD大脑中存在Abeta的可溶性毒性形式；这些形式最近被确定为Abeta的寡聚集合体。目前，人们认为阿尔茨海默病的发病始于可溶性Abeta寡聚体引起的突触功能障碍。这一假说被称为寡聚体假说，基于以下观察：AD大脑中的Abeta寡聚体水平很高。生理浓度的外源性Abeta寡聚体在体内会导致突触和认知功能障碍，在体外会导致突触丢失和神经元死亡。此外，我们观察到在AD患者中发现的淀粉样前体蛋白E693Delta突变通过增加Abeta寡聚体的形成而不诱导Abeta纤维或老年斑的形成而导致疾病。目前，老年斑的形成被认为是为了保护神经元免受可扩散的Abeta寡聚体的毒性，将它们隔离在沉积物中。因此，可溶性Abeta寡聚体在AD不溶性Abeta纤维的病因学中起着更重要的作用。
Amyloid beta-peptide (Abeta) is a key molecule in Alzheimer disease (AD). Cerebral deposition of Abeta was earlier thought to initiate the pathological cascade of AD, including the formation of senile plaques and neurofibrillary tangles, neuronal loss, and dementia. According to the classical amyloid hypothesis, the aggregation of Abeta into insoluble beta-sheet fibrils plays an important role in its neurotoxicity. However, this hypothesis is paradoxical: The concentrations of Abeta required for fibrillization and neurotoxicity are higher than its physiological concentrations. Cognitive decline in AD patients is not correlated with the levels of senile plaque formation or insoluble Abeta formation; instead it correlates with the levels of synapse loss and the levels of soluble Abeta. These observations suggest the existence of soluble toxic forms of Abeta in AD brains; these forms have recently been identified to be oligomeric assemblies of Abeta. At present, AD is believed to begin with synaptic dysfunction caused by soluble Abeta oligomers. This hypothesis termed the oligomer hypothesis, is based on the following observations: The levels of Abeta oligomers are high in AD brains. Exogenous Abeta oligomers at physiological concentrations cause synaptic and cognitive dysfunction in vivo and synapse loss and neuronal death in vitro. Furthermore, we observed that the E693delta mutation in the amyloid precursor protein found in AD patients causes disease by increasing the formation of Abeta oligomers without inducing the formation of Abeta fibrils or senile plaques. Currently, senile plaque formation is thought to occur in order to protect neurons from the toxicity of diffusible Abeta oligomers by sequestering them into deposits. Thus, soluble Abeta oligomers play a more important role in the etiology of AD insoluble Abeta fibrils.