Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers
Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers
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DOI：
10.1073/pnas.0809158106
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发表时间：
2009-02-10
影响因子：
11.1
通讯作者：
Klein, William L.
中科院分区：
文献类型：
--
作者：
De Felice, Fernanda G.;Vieira, Marcelo N. N.;Klein, William L.
早期阿尔茨海默病（AD）中严重记忆丧失的潜在突触退化被认为是由可溶性淀粉样蛋白β（A β）寡聚体引起的。从机制上讲，可溶性A β寡聚体，也称为A β衍生的可扩散配体（ADDL），充当高度特异性的致病配体，结合到位于特定突触的位点。这种结合引发氧化应激、突触棘的丧失以及对可塑性和记忆至关重要的受体的异位再分布。我们在这里报告存在一种保护机制，自然屏蔽突触对ADDL诱导的恶化。在海马神经元的成熟培养物中研究突触病理学。在脊柱缺失之前，ADDL通过对钙钙调蛋白依赖性激酶II（CaMKII）和酪蛋白激酶II（CK 2）抑制敏感的机制引起质膜胰岛素受体（IR）的主要下调。最重要的是，这种表面IR的丧失，以及ADDL诱导的氧化应激和突触棘退化，可以完全由胰岛素预防。在次最大胰岛素剂量下，罗格列酮（一种用于治疗2型糖尿病的胰岛素增敏药）可增强保护作用。胰岛素保护的机制需要致病ADDL结合的显着减少。令人惊讶的是，当IR酪氨酸激酶活性被抑制时，胰岛素未能阻断ADDL结合;事实上，结合的显著增加是由IR抑制引起的。因此，胰岛素的保护作用来自ADDL结合位点的IR信号依赖性下调，而不是配体竞争。这一发现表明，胰岛素可以减轻突触对ADDL的脆弱性，这表明支持大脑胰岛素信号传导，这可能会随着衰老和糖尿病而下降，可能具有减缓或阻止AD发病的巨大潜力。
Synapse deterioration underlying severe memory loss in early Alzheimer's disease ( AD) is thought to be caused by soluble amyloid beta (A beta) oligomers. Mechanistically, soluble A beta oligomers, also referred to as A beta-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.