Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism
Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism
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DOI：
10.1038/nn.2100
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发表时间：
2008-05-01
影响因子：
25
通讯作者：
Di Paolo, Gilbert
中科院分区：
文献类型：
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作者：
Berman, Diego E.;Dall'Armi, Claudia;Di Paolo, Gilbert
由淀粉样β肽（A β）的寡聚体组装引起的突触功能障碍与阿尔茨海默病中的认知缺陷有关。在这里，我们发现原代皮层神经元与寡聚A β孵育降低了磷脂酰肌醇-4，5-二磷酸（PtdIns（4，5）P-2）的水平，这是一种调节神经元功能关键方面的磷脂。A β对PtdIns（4，5）P-2代谢的不稳定作用是Ca 2+依赖性的，并且在来自Synj 1单倍不足小鼠的神经元中未观察到。该基因编码synaptojanin 1，其是脑中和突触处的主要PtdIns（4，5）P-2磷酸酶。我们还发现，在Synj 1（+/-）小鼠的脑片中，A β对海马长时程增强的抑制作用受到强烈抑制，这表明A β诱导的突触功能障碍可以通过维持大脑中正常PtdIns（4，5）P-2平衡的治疗来改善。
Synaptic dysfunction caused by oligomeric assemblies of amyloid-beta peptide (A beta) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric A beta decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P-2), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of A beta on PtdIns(4,5)P-2 metabolism was Ca2+-dependent and was not observed in neurons that were derived from mice that are haploinsufficient for Synj1. This gene encodes synaptojanin 1, the main PtdIns(4,5)P-2 phosphatase in the brain and at the synapses. We also found that the inhibitory effect of A beta on hippocampal long-term potentiation was strongly suppressed in slices from Synj1(+/-) mice, suggesting that A beta-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P-2 balance in the brain.