Advances on the understanding of the origins of synaptic pathology in AD.
Advances on the understanding of the origins of synaptic pathology in AD.
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DOI：
10.2174/138920207783769530
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发表时间：
2007-12
期刊：
影响因子：
2.6
通讯作者：
Lacor PN
中科院分区：
文献类型：
--
作者：
Lacor PN
尽管阿尔茨海默病（AD）在一个世纪前首次被发现，但我们仍然面临着患者一生中缺乏明确诊断的问题，并且无法开出治愈性治疗方法。然而，在过去的 10 年里，关于 AD 发病机制的主要假设发生了“修正”，人们希望预见到可能的治疗方法。 AD不再被认为是一种不可逆转的疾病。对将淀粉样蛋白原纤维描述为神经毒素的经典 β-淀粉样蛋白级联进行了重大改进，以整合关键科学证据，证明 AD 早期发生的第一个病理事件影响突触功能和维持。与突触丧失完全兼容的概念是 AD 的最佳病理相关性，而不是其他描述的神经病理学标志（淀粉样蛋白斑、神经原纤维缠结或神经元死亡）。转基因AD小鼠中针对β-淀粉样蛋白的免疫治疗实验证实了突触改变可能被逆转，从而提供潜在的治愈性的观点，在这些小鼠中，尽管淀粉样斑块负担没有减少，但认知功能得到了改善。更新的淀粉样蛋白级联现在整合了由可溶性 Aβ-寡聚物触发的突触故障。对于毒性最强的 Aβ 构象，无论是其产生位点，还是其细胞外与细胞内作用，尚未达成共识。有证据表明，可溶性 Aβ 寡聚物或 ADDL 选择性地与神经元的突触位点结合，并引发突触组成和形态的重大变化，最终导致树突棘损失。然而，确切的机制尚未完全了解，但怀疑涉及一些膜受体。
Although Alzheimer’s disease (AD) was first discovered a century ago, we are still facing a lack of definitive diagnosis during the patient’s lifetime and are unable to prescribe a curative treatment. However, the past 10 years have seen a “revamping” of the main hypothesis about AD pathogenesis and the hope to foresee possible treatment. AD is no longer considered an irreversible disease. A major refinement of the classic β-amyloid cascade describing amyloid fibrils as neurotoxins has been made to integrate the key scientific evidences demonstrating that the first pathological event occurring in AD early stages affects synaptic function and maintenance. A concept fully compatible with synapse loss being the best pathological correlate of AD rather than other described neuropathological hallmarks (amyloid plaques, neurofibrillary tangles or neuronal death). The notion that synaptic alterations might be reverted, thus offering a potential curability, was confirmed by immunotherapy experiments targeting β-amyloid protein in transgenic AD mice in which cognitive functions were improved despite no reduction in the amyloid plaques burden. The updated amyloid cascade now integrates the synapse failure triggered by soluble Aβ-oligomers. Still no consensus has been reached on the most toxic Aβ conformations, neither on their site of production nor on their extra- versus intra-cellular actions. Evidence shows that soluble Aβ oligomers or ADDLs bind selectively to neurons at their synaptic loci, and trigger major changes in synapse composition and morphology, which ultimately leads to dendritic spine loss. However, the exact mechanism is not yet fully understood but is suspected to involve some membrane receptor(s).
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影响因子：
5.3
作者：
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