NACP/ALPHA SYNUCLEIN & DEGERATION IN LEWY BODY

NACP是阿尔茨海默病（AD）淀粉样蛋白（α -突触核蛋白）非a组分的前体，是一种在AD斑块中积累的突触分子。最近的研究表明NACP的突变与家族性帕金森病有关，路易小体对该分子的抗体具有免疫反应性。在此背景下，本项目的中心假设是NACP的异常积累/区隔化参与了路易体病（LBD）的神经退行性变过程。本研究的主要目的是为了更好地了解NACP异常积累导致神经退行性变的机制。为此，我们提出以下具体目的：1)确定LBD患者脑内NACP/ α -突触核蛋白异常积累与神经退行性变的关系。我们推测，在LBD中，NACP/ α -突触核蛋白的异常积累将导致中边缘、中皮层和纹状体神经系统细胞的神经变性。为此，我们拟确定LBD患者死后大脑（额叶、颞叶、海马、基底神经节、扣带和中脑）突触、神经元和神经突中NACP/ α -突触核蛋白水平与细胞计数、突触密度和凋亡之间的关系。2)建立体内模型，探讨NACP/ α -突触核蛋白促进神经退行性变的机制。我们假设异常的NACP/ α -突触核蛋白积累导致NACP/ α -突触核蛋白的过度表达将导致转基因（tg）小鼠突触损伤和神经元细胞死亡。此外，我们假设突变的NACP/ α -突触核蛋白可能加速这一过程。为此，我们提出在血小板衍生生长因子（PDGF）启动子的控制下，研究过表达突变型和野生型人NACP/ α -突触核蛋白的年轻和年老tg小鼠大脑中神经变性的模式。3)确定与AD相关的危险因素是否会增加tg小鼠对NACP/ α -突触核蛋白诱导的神经变性的易感性。我们假设已知的AD遗传风险因素，如载脂蛋白E4等位基因（ApoEepsilon4）和淀粉样前体蛋白（APP）突变的存在，会增强NACP/ α -突触核蛋白tg小鼠与apoe缺陷（敲除）、ApoEepsilon3或E4 tg小鼠以及淀粉样前体蛋白（APP）野生型和突变型tg小鼠杂交。综上所述，这些研究将有助于更好地描述LBD神经退行性变的分子和细胞机制。模型和范例的发展也将有助于确定潜在的目标，将防止神经退行性疾病的神经元细胞损伤。

NACP, the precursor of non-A component of Alzheimer's disease (AD) amyloid (alpha-synuclein) is a synaptic molecule that accumulates in AD plaques. Recent studies have shown that a mutation in NACP is associated with familial Parkinson disease and that Lewy bodies are immunoreactive with antibodies against this molecule. In this context, the central hypothesis of this project is that abnormal accumulation/compartmentalization of NACP is involved in the process of neurodegeneration in Lewy body disease (LBD). The main objective of this proposal is to better understand the mechanisms through which abnormal accumulation of NACP leads to neurodegeneration. For this purpose, we propose the following Specific Aims: 1) To determine the relationship between abnormal NACP/alpha- synuclein accumulation and neurodegeneration in the brains of patients with LBD. We hypothesize that in LBD abnormal accumulation of NACP/alpha- synuclein will result in neurodegeneration of cells within the mesolimbic, mesocortical and striatonigral systems. For this purpose, we propose to determine the relationship between NACP/alpha-synuclein levels in synapses, neurons and neurites and cell counts, synapse density and apoptosis in postmortem brains (frontal, temporal, hippocampus, basal ganglial, cingulate and mesencephalon) from patients with LBD. 2) To develop in vivo models to investigate mechanisms which NACP/alpha- synuclein promotes neurodegeneration. We hypothesize that abnormal NACP/alpha-synuclein accumulation resulting over-expression of NACP/alpha-synuclein will result in synaptic damage and neuronal cell death in transgenic (tg) mice. Furthermore, we postulate that mutant NACP/alpha-synuclein might accelerate this process. For this purpose we propose to investigate the patterns of neurodegeneration in the brains of young and old tg mice over-expressing mutant and wildtype human NACP/alpha-synuclein under the control of the platelet-derived growth factor (PDGF) promoter. 3) To determine if risk factors associated with AD increase susceptibility to NACP/alpha-synuclein-induced neurodegeneration in tg mice. We hypothesize that known genetic risk factors for AD such as the presence of apolipoprotein E4 allele (ApoEepsilon4) and amyloid precursor protein (APP) mutations will enhance NACP/alpha-synuclein tg mice will be crossbred with apoE-deficient (knockout), ApoEepsilon3 or E4 tg mice, and with amyloid precursor protein (APP) wildtype and mutant tg MICE. Taken together these studies will help to better delineate the molecular and cellular mechanisms involved in neurodegeneration in LBD. The models and paradigms developed will also help to identify potential targets that will prevent neuronal cell injury in neurodegenerative disorders.