GERIATRIC DEMENTIA RESEARCH CLINIC

在拟议的研究中要检验的中心假设是， 阿尔茨海默病中的细胞异常表达于 在非神经组织的细胞水平上进行研究， 大脑 这些研究集中在组织培养模型上， 培养的皮肤成纤维细胞。 项目1将测试 成纤维细胞正常表达抗原的培养系统 与培养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]），并且其中 来自阿尔茨海默病患者的成纤维细胞的比例与抗 与对照组细胞相比， 的分子 负责这些反应将被表征。 的关系 这些分子在培养物中积累到生物年龄， 阿尔茨海默病中描述的线粒体和其他代谢异常 细胞将被确定，和临床特异性和诊断 测试了这一观察结果的效用。 项目2将检查信号 内稳态中的转导机制，磷酸肌醇级联，以及 环AMP）。 重点将放在阐明基本机制上 包括与生物年龄的关系以及 项目1。 项目5将比较阿尔茨海默病的线粒体代谢 和对照细胞，确定报告的机制， 线粒体异常，特别是阿尔茨海默氏症的脆弱性， 对照细胞，跟进异常DNA修复的报告。 Project 7 将明确神经肽可塑性丧失的潜在机制 在老化的上级颈神经元的文化;它涉及到其他 研究表明，由于年龄是阿尔茨海默病的一个主要危险因素。 临床 试点项目将检查阿尔茨海默病患者的书写异常。 这些核心将提供支助活动，包括为所有 研究了在严格控制下生长的细胞的成纤维细胞， 条件下，阿尔茨海默病和对照细胞的生物学年龄相匹配， 文化以及供体的实际年龄和性别。

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.