β-Amyloid Monomers Are Neuroprotective
β-Amyloid Monomers Are Neuroprotective
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DOI：
10.1523/jneurosci.1736-09.2009
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发表时间：
2009-08-26
影响因子：
5.3
通讯作者：
Copani, Agata
中科院分区：
文献类型：
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作者：
Giuffrida, Maria Laura;Caraci, Filippo;Copani, Agata
42-aa长的β-淀粉样蛋白-A β（1-42）-被认为在阿尔茨海默病（AD）的发病机制中起核心作用（沃尔什和Selkoe，2007）。来自AD脑的数据（Shankar等人，2008）、转基因APP（淀粉样前体蛋白）过表达小鼠（Lesne等人，2006）和用合成A β肽处理的神经元培养物（Lambert et al.，1998）表明，A β（1-42）单体自缔合成可溶性低聚物是神经毒性所必需的。单体A β（1-42）的功能尚不清楚。A β（1-42）存在于正常个体的大脑和CSF中的证据表明，该肽具有生理活性（Shoji，2002）。在这里，我们表明，合成的A β（1-42）单体支持营养剥夺条件下发育中的神经元的存活，并保护成熟的神经元免受兴奋性毒性死亡，这一过程有助于与AD相关的整体神经变性。A β（1-42）单体的神经保护作用由PI-3-K（磷脂酰肌醇-3-激酶）途径的激活介导，并涉及IGF-1（胰岛素样生长因子-1）受体和/或胰岛素超家族的其他受体的刺激。有趣的是，携带与熟悉的AD相关的北极突变（E22 G）的A β（1-42）的单体（Nilsberth et al.，2001）没有神经保护作用。我们认为A β（1-42）的病理性聚集也可能通过剥夺A β（1-42）单体的保护活性而引起神经变性。在设计旨在降低A β负荷的治疗时，应考虑神经元死亡的“功能丧失”假设。
The 42-aa-long beta-amyloid protein-A beta(1-42)-is thought to play a central role in the pathogenesis of Alzheimer's disease (AD) (Walsh and Selkoe, 2007). Data from AD brain (Shankar et al., 2008), transgenic APP (amyloid precursor protein)-overexpressing mice (Lesne et al., 2006), and neuronal cultures treated with synthetic A beta peptides (Lambert et al., 1998) indicate that self-association of A beta(1-42) monomers into soluble oligomers is required for neurotoxicity. The function of monomeric A beta(1-42) is unknown. The evidence that A beta(1-42) is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic A beta(1-42) monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration associated with AD. The neuroprotective action of A beta(1-42) monomers was mediated by the activation of the PI-3-K (phosphatidylinositol-3-kinase) pathway, and involved the stimulation of IGF-1 (insulin-like growth factor-1) receptors and/or other receptors of the insulin superfamily. Interestingly, monomers of A beta(1-42) carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of A beta(1-42) may also cause neurodegeneration by depriving neurons of the protective activity of A beta(1-42) monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing A beta burden.