NEUROPEPTIDE/CHOLINERGIC FUNCTION/ALZHEIMER'S DISEASE

阿尔茨海默病(AD)最常见的神经化学病理 痴呆症的病因日益受到人们的重视。现在是时候了 显然，特定的化学定义的神经递质系统 在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神经元和两组神经肽细胞： 大脑皮层内含生长抑素和促肾上腺皮质激素释放激素的细胞。其他 肽能神经元，如含有缩胆囊素和 血管活性肠肽显然是不受影响的。在现在 我们寻求继续审查竞争性续签申请 详细地说，使用从 快速尸检程序(死亡后20-60分钟)。通过测量 神经元完整性、神经元活性的标志物(高亲和力胆碱 摄取)、胆碱转运体本身、受体数量和亲和力， 以及第二信使和第三信使应答(蛋白质 磷酸化)，胆碱能神经传递的动态 在组织学证实的AD和AD的几个大脑区域进行评估 年龄和性别匹配的对照组。此外，我们将继续我们的工作 阿尔茨海默病中的肽能系统(SRIF和CRF)包括 脑脊液与脑组织血药浓度关系的研究 这些多肽。此外，还将测量SRIF受体亚型，如 会影响这些受体的功能反应。我们还将确定 异常多动症的存在与相关因素的关系 蛋白，ALZ 68，以及ACh和肽能神经元的变化。我们 也应该仔细观察AD中含有GABA的神经元的变化。这个 这些研究中的大多数都是可行的，因为它具有独特的可用性 快速尸检组织-我们的中心是世界上唯一的 进行这一程序。这些研究将提供新的数据， 很可能导致开发一种合理的患者药物疗法 使用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.