NEUROPEPTIDE/CHOLINERGIC FUNCTION/ALZHEIMER'S DISEASE

阿尔茨海默病（AD）的神经化学病理学，最常见的 痴呆症的病因，越来越受到人们的关注。 现在 显然，特定的化学定义的神经递质系统是 病理上与这种神经退行性疾病有关 神经元 受影响的包括基底前脑中的胆碱能神经元， 含GABA的神经元和两组含神经肽的细胞： 生长抑素和CRF细胞在大脑皮层。 其他 肽能神经元，如含有胆囊收缩素的那些， 血管活性肠肽明显幸免。 本 我们寻求继续审查竞争性续期申请， 详细地，使用组织中获得的胆碱能神经元的动态状态， 快速尸检程序（死亡后20-60分钟）。 通过测量 神经元完整性、神经元活性（高亲和力胆碱 摄取），胆碱转运蛋白本身，受体数量和亲和力， 以及第二信使和第三信使反应（蛋白质 磷酸化），胆碱能神经传递的动态状态将 在组织学证实的AD的几个脑区域中进行评估， 年龄和性别匹配的对照组。 此外，我们将继续我们的工作， 对阿尔茨海默病中的肽能（SRIF和CRF）系统的影响，包括 评估CSF和脑浓度之间的关系 这些肽。 此外，将测量SRIF受体亚型，如 将这些受体的功能反应。 我们还将确定 与AD相关的异常 蛋白，Alz 68，以及ACh和肽能神经元的改变。 我们 还将仔细检查AD中含有GABA的神经元的改变。 的 这些研究中的大多数是可行的，因为其独特的可用性 我们的中心是世界上唯一一个 进行这个程序。 这些研究将提供新的数据， 很可能导致患者合理的药物治疗的发展 与AD

The neurochemical pathology of Alzheimer's disease (AD), the most common cause of dementia, has received increasingly more attention. It is now evident that specific chemically-defined neurotransmitter systems are pathologically involved in this neurodegenerative disorder. Neurons affected include cholinergic neurons in the basal forebrain, GABA-containing neurons and two groups of neuropeptide-containing cells: somatostatin- and CRF-containing cells in the cerebral cortex. Other peptidergic neurons such as those containing cholecystokinin and vasoactive-intestinal peptide are apparently spared. In the present competitive renewal application we seek to continue to scrutinize in detail, the dynamic state of cholinergic neurons using tissue obtained in the Rapid Autopsy Procedure (20-60 min after death). By measuring markers of neuronal integrity, neuronal activity (high affinity choline uptake), the choline transporter itself, receptor number and affinity, and second messenger as well as third messenger responses (protein phosphorylation), the dynamic state of cholinergic neurotransmission will be assessed in several brain regions from histologically-confirmed AD and age- and sex-matched controls. In addition, we shall continue our work on peptidergic (SRIF and CRF) systems in Alzheimer's disease including assessment of the relationship between CSF and brain concentrations of these peptides. Moreover, SRIF receptor subtypes will be measured, as will functional responses of these receptors. We shall also determine the relationship between the presence of the abnormal ADassociated protein, Alz 68, and the alterations in ACh and peptidergic neurons. We shall also scrutinize alterations in GABA-containing neurons in AD. The majority of these studies are feasible because of the unique availability of the rapid autopsy tissue - our center is the only one in the world conducting this procedure. These studies will provide novel data that may well result in the development of a rational drug therapy in patients with AD.