Han H, Weinreb P H, Lansbury P T
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
Chem Biol. 1995 Mar;2(3):163-9. doi: 10.1016/1074-5521(95)90071-3.
NAC is a 35-amino-acid peptide which has been isolated from the insoluble core of Alzheimer's disease (AD) amyloid plaque. It is a fragment of alpha-synuclein (or NACP), a neuronal protein of unknown function. We noted a striking sequence similarity between NAC, the carboxyl terminus of the beta-amyloid protein, and a region of the scrapie prion protein (PrP) which has been implicated in amyloid formation.
NAC was prepared by chemical synthesis and was found to form amyloid fibrils via a nucleation-dependent polymerization mechanism. NAC amyloid fibrils effectively seed beta 1-40 amyloid formation. Amyloid fibrils comprising peptide models of the homologous beta and PrP sequences were also found to seed amyloid formation by NAC.
The in vitro model studies presented here suggest that seeding of NAC amyloid formation by the beta-amyloid protein, or seeding of amyloid fibrils of the beta-amyloid protein by NAC, may occur in vivo. Accumulation of ordered NAC aggregates in the synapse may be responsible for the neurodegeneration observed in AD and the prion disorders. Alternatively, neurodegeneration may be caused by the loss of alpha-synuclein (NACP) function.
NAC是一种由35个氨基酸组成的肽，已从阿尔茨海默病（AD）淀粉样斑块的不溶性核心中分离出来。它是α-突触核蛋白（或NACP）的一个片段，α-突触核蛋白是一种功能未知的神经元蛋白。我们注意到NAC、β-淀粉样蛋白的羧基末端与羊瘙痒病朊病毒蛋白（PrP）的一个与淀粉样蛋白形成有关的区域之间存在显著的序列相似性。
通过化学合成制备了NAC，发现其通过成核依赖性聚合机制形成淀粉样纤维。NAC淀粉样纤维有效地引发β1-40淀粉样蛋白的形成。还发现由同源β和PrP序列的肽模型组成的淀粉样纤维可引发NAC的淀粉样蛋白形成。
此处呈现的体外模型研究表明，β-淀粉样蛋白引发NAC淀粉样蛋白的形成，或NAC引发β-淀粉样蛋白的淀粉样纤维的形成，可能在体内发生。突触中有序NAC聚集体的积累可能是AD和朊病毒疾病中观察到的神经退行性变的原因。或者，神经退行性变可能是由α-突触核蛋白（NACP）功能丧失引起的。
