Synaptic Dysfunction in Alzheimer's Disease
Synaptic Dysfunction in Alzheimer's Disease
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DOI：
10.1007/978-3-7091-0932-8_25
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Di Luca, Monica
中科院分区：
文献类型：
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作者：
Marcello, Elena;Epis, Roberta;Di Luca, Monica
淀粉样肽（A β）的产生是导致阿尔茨海默病（AD）的级联反应的开始。淀粉样前体蛋白（APP）以及β-和γ-分泌酶是参与A β产生的主要参与者，而APP上的α-分泌酶裂解可防止A β沉积。最近的研究表明，A β肽的可溶性组装状态可以通过在没有显著神经变性的情况下破坏突触功能而引起认知问题。因此，目前的研究调查了这些不同的可溶性A β组装体在引起突触功能障碍和认知缺陷中的相对重要性。已经鉴定了几种A β寡聚体靶点和负责A β诱导的突触失败的细胞机制。第一个也是最重要的机制是A β功能的毒性获得，这是由于自缔合和获得能够产生新相互作用的新结构导致可塑性受损。其他情况则认为A β具有正常的生理作用。一方面，A β不足可能导致正常功能丧失，而A β过量可能会导致功能障碍。这是如何发生的，以及A β的突触作用的主要靶点是什么仍然有待充分理解，这肯定是未来AD研究的主要挑战之一。
Generation of amyloid peptide (A beta) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as beta- and gamma-secretases, is the principal player involved in A beta production, while cc-secretase cleavage on APP prevents A beta deposition. Recent studies suggested that soluble assembly states of A beta peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble A beta assemblies in causing synaptic dysfunction and cognitive deficits. Several A beta oligomers targets and cellular mechanisms responsible of A beta-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for A beta which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that A beta has a normal physiological role. On the one hand, insufficient A beta could lead to a loss of normal function, whereas excess A beta may precipitate dysfunction. How this occurs and which the main target/s is/are for the synaptic action of A beta remains to be fully understood and would certainly represent one of the main challenges to future AD research.