GERIATRIC DEMENTIA RESEARCH CLINIC

在拟议的研究中要检验的中心假设是关键 阿尔茨海默病的细胞异常表现为 在非神经组织的细胞水平上进行有用的研究 大脑。这些研究主要集中在组织培养模型上，特别是 培养的皮肤成纤维细胞。项目1将测试以下各项的有效性和实用性 成纤维细胞似乎能正常表达抗原的培养系统 与培养中或体内的神经元相关(神经元特异性烯醇化酶 [NSE]和神经丝[NF])，其中显著更高的 阿尔茨海默病患者成纤维细胞与抗体反应的比例 成对的螺旋细丝比来自对照的细胞更多。这些分子 将对这些反应负责的人进行表征。两人之间的关系 这些分子在培养中积累到生物学年龄，并 阿尔茨海默病患者的线粒体和其他代谢异常 细胞将被确定，并具有临床特异性和诊断价值 这一观察结果的有效性得到了检验。项目2将检查信号 动态平衡中的转导机制，肌醇磷酸级联，以及 循环AMP)。重点将放在阐明基本机制上 包括与生物学年龄的关系以及与 项目1.项目5将比较阿尔茨海默病患者的线粒体代谢 和控制细胞，确定报告的 线粒体异常，特别是阿尔茨海默病和老年痴呆症的脆性 对照细胞，跟踪异常DNA修复的报告。项目7 将确定神经肽可塑性丧失的机制 在培养的颈上神经细胞老化中；它与另一种 学习，因为年龄-是阿尔茨海默病的主要危险因素。一家诊所 Pilot Project将检查阿尔茨海默氏症患者的书写异常。 这些核心将提供支助活动，包括为所有人提供 细胞成纤维细胞在精心控制下生长的研究 在阿尔茨海默病和对照细胞生物学年龄匹配的情况下 文化以及捐赠者的年龄和性别。

The central hypothesis to be tested in the proposed studies is that key cellular abnormalities in Alzheimer's disease are expressed in and can usefully be studied at the cellular level in non-neural tissues as well as the brain. The studies focus on tissue culture models and specifically cultured skin fibroblasts. Project 1 will test the validity and utility of a culture system in which fibroblasts appear to express antigens normally associated with neurons in culture or in vivo (neuron-specific enolase [NSE] and neurofilaments [NF]), and in which a significantly higher proportion of fibroblasts from Alzheimer patients react with antibodies to paired helical filaments than do cells from controls. The molecules responsible for these reactions will be characterized. The relation of the accumulation of those molecules to biological age in culture and to mitochondrial and other metabolic abnormalities described in Alzheimer cells will be determined, and the clinical specificity and diagnostic utility of this observation tested. Project 2 will examine signal transduction mechanisms in homeostasis, the inositol phosphate cascade, and cyclic AMP). The emphasis will be on elucidating basic mechanisms including relationships to biological age and to mechanisms studied in Project 1. Project 5 will compare mitochondrial metabolism in Alzheimer and control cells, determining the mechanisms underlying the reported mitochondrial abnormalities and particularly the fragility in Alzheimer and control cells, following up on reports of abnormal DNA repair. Project 7 will define the mechanisms underlying the loss of neuropeptide plasticity in aging superior cervical neurons in culture; it relates to the other studies, since age-is a major risk factor Alzheimer's disease. A clinical Pilot Project will examine writing abnormalities in Alzheimer patients. The cores will provide support activities, including the provision for all studies of fibroblasts of cells grown under meticulously controlled conditions, with Alzheimer and control cells matched for biological age in culture as well as chronological age and gender of donor.