The Role of Cholinergic Functions in Alzheimer's Disease

胆碱能功能在阿尔茨海默病中的作用

• 批准号: 7055226
• 负责人: Zhen Yan
• 金额: $ 33.46万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055226
• 关键词: Alzheimer' s disease; GABA receptor; SDS polyacrylamide gel electrophoresis; acetylcholine; amyloid proteins; anticholinergic agent; biological signal transduction; cognition; electrophysiology; frontal lobe /cortex; genetically modified animals; immunoprecipitation; insulin; laboratory mouse; laboratory rat; membrane potentials; memory; muscarinic receptor; neural transmission; neuropharmacology; neurotransmitters; phosphatidylinositol 3 kinase; polymerase chain reaction; protein kinase C; protein structure function; receptor expression

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating neurodegenerative disorder that afflicts millions of people worldwide. Two major features of AD are: (1) degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in cortex and hippocampus; (2) extracellular protein aggregates containing beta-amyloid peptides (Abeta) in these cholinergic target areas. So far, the most effective therapeutic strategy in AD treatment is to enhance cholinergic transmission. Neuromodulatory functions of the cholinergic system are mainly mediated by muscarinic receptors (mAChRs). It has long been recognized that mAChRs are crucial for the control of high-level cognitive processes. Drugs that activate mAChRs are helpful in ameliorating cognitive deficits of AD. Despite the discovery of correlation between cholinergic hypofunction and AD, the cellular and molecular mechanisms underlying the function and dysfunction of mAChRs in normal cognition and dementia remain elusive. The long-term goals of this project are to understand (1) how muscarinic signaling is involved in the regulation of neuronal activity and synaptic transmission in frontal cortex, which is critical for learning and memory under normal condition; and (2) how this regulation is altered in animal models that simulate cognitive and memory impairments associated with AD. Recent evidence indicates that GABAergic inhibition in frontal cortex plays an important role in "working memory" by controlling the timing of neuronal activities during cognitive operations. We hypothesize that the GABAA receptor channel is potentially a key cellular substrate for muscarinic signaling in cognition and memory, and disruption of its regulation by mAChRs in AD might contribute to the cognitive impairment. Transgenic mice overexpressing a mutant gene for beta-amyloid precursor protein (APP) show behavioral and histopathological abnormalities resembling AD, and therefore will be used as an AD model in our experiments. Emerging evidence suggests that Abeta plays pleiotropic roles in the regulation of cholinergic functions in cortex. We hypothesize that the muscarinic modulation of GABAA receptor function is lost in AD models due to the interference of Abeta on muscarinic signaling. Combined electrophysiological, pharmacological, biochemical and molecular analyses will be used to test these hypotheses. This research would shed some light on how the two prominent features of AD (cholinergic hypofunction and Abeta accumulation) may be linked to cause cognitive impairments. Such knowledge should offer important insights into the cellular and molecular basis of AD and the development of new pharmacological agents in the treatment of this disease.

描述（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的神经退行性疾病，困扰着全世界数百万人。 AD的两个主要特征是：（1）基底前脑胆碱能神经元变性，导致皮层和海马胆碱能功能缺陷； (2)这些胆碱能靶区域中含有β-淀粉样肽(Abeta)的细胞外蛋白聚集体。迄今为止，AD治疗最有效的治疗策略是增强胆碱能传递。胆碱能系统的神经调节功能主要由毒蕈碱受体（mAChR）介导。人们早就认识到 mAChR 对于控制高级认知过程至关重要。激活 mAChR 的药物有助于改善 AD 的认知缺陷。尽管发现胆碱能功能减退与 AD 之间存在相关性，但 mAChR 在正常认知和痴呆中功能和功能障碍的细胞和分子机制仍然难以捉摸。 该项目的长期目标是了解（1）毒蕈碱信号如何参与额叶皮层神经元活动和突触传递的调节，这对正常情况下的学习和记忆至关重要； (2) 在模拟与 AD 相关的认知和记忆障碍的动物模型中，这种调节是如何改变的。 最近的证据表明，额叶皮层的 GABA 能抑制通过控制认知操作过程中神经元活动的时间，在“工作记忆”中发挥重要作用。我们假设 GABAA 受体通道可能是认知和记忆中毒蕈碱信号传导的关键细胞底物，AD 中 mAChR 对其调节的破坏可能会导致认知障碍。过度表达β-淀粉样前体蛋白（APP）突变基因的转基因小鼠表现出类似于AD的行为和组织病理学异常，因此将在我们的实验中用作AD模型。新的证据表明 Abeta 在皮质胆碱能功能的调节中发挥多效性作用。我们推测，由于 Abeta 对毒蕈碱信号传导的干扰，GABAA 受体功能的毒蕈碱调节在 AD 模型中丢失。结合电生理学、药理学、生化和分子分析将用于检验这些假设。这项研究将揭示 AD 的两个突出特征（胆碱能功能减退和 Abeta 积累）如何与导致认知障碍相关。这些知识应该为 AD 的细胞和分子基础以及治疗这种疾病的新药物的开发提供重要的见解。