FOREBRAIN NEUROTROPIC ABNORMALITIES & MILD COGNITIVE IMPAIRMENT IN THE ELDERLY

前脑神经营养异常

• 批准号: 6234633
• 负责人: ELLIOTT Jay MUFSON
• 金额: $ 17.73万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234633
• 关键词: aging; bioassay; choline acetyltransferase; clinical research; cognition disorders; human old age (65+); human tissue; immunocytochemistry; in situ hybridization; neural degeneration; neuropathology; neurotrophic factors; prosencephalon

Although older (>65 years) individuals manifest cognitive impairments ranging from mild abnormalities to overt dementia, the molecular and cellular substrates that account for this variation remain to be defined. Several reports indicate cholinergic hypofunction in elderly humans. However, none of these studies related cholinergic changes to cognitive status. The importance of this system to human cognition is underscored by studies in Alzheimer's disease (AD) where the most consistent neurochemical abnormality to crrelate with cognitive impairment is decreases in cortical choline acetyltransferase (ChAT). Interestingly, AD patients with an increased gene dose for the apolipoprotein (ApoE) e4 allele (a genetic risk factor for AD) exhibit greater cholinergic deficts (i.e., cortical ChAT reduction and cholinergic basal forebrain(CBF) neuron loss) and are less responsive to anticholinesterase drugs. The status of the CBF system and the association of the ApoE genotype in aged individuals with mild cognitive impairment (MCI), however, is still unknown. We do know, however, that cortical ChAT levels decrease with aging in the human brain. Therefore, Specific Aim 1 will establish whether CBF degneration including reduction in cortical ChAT is associated with cognitive impairment in individuals with MCI. Findings from our group, have led to the hypothesis that the vulnerability of CBF neurons results from defects in the binding or transport of NGF and its high affinity signal transducing trkA receptor which, in turn, leads to impaired NGF trophic support in AD. Support for this suggestion is derived from our studies demonstrating that NGF protein- immunoreactivity and the message for its high affinity trkA receptors are decreased within CBF neurons whereas, cortical NGF protein is increased in AD. Taken together these observations suggest that the NGF protein accumulates within the cortex, because it is not transported in a normal fashion to CBF consumer perikarya where it is needed for its trophic effects to occur. Specific Aims 2-3 will determine whether impaired NGF transport is also associated with age-related MCI in the elderly. These studies will employ modern stereology, bioassay, immunohistochemistry and in situ hybridization procedures. The results of these investigations will have major implications for therapeutic strategies in aging and MCI and the role of genetics in considering these issues.

尽管年龄较大（> 65岁）的人表现出认知障碍 从轻度异常到明显的痴呆，分子和 解释这种变化的细胞基材仍有待定义。 几份报告表明，老年人的胆碱能功能功能低下。 但是，这些研究都没有将胆碱能变化与认知的变化有关 地位。 该系统对人类认知的重要性是 受阿尔茨海默氏病（AD）的研究强调 一致的神经化学异常，以认知能力 皮质胆碱乙酰转移酶（CHAT）的损伤减少。 有趣的是，基因剂量增加的AD患者 载脂蛋白（APOE）E4等位基因（AD的遗传危险因素） 更大的胆碱能符号（即减少皮质聊天和 胆碱能基础前脑（CBF）神经元丧失），反应较差 抗胆碱酯酶药物。 CBF系统的状态和 apoE基因型在年龄较小的个体中的关联 但是，认知障碍（MCI）仍然未知。 我们知道， 但是，皮质聊天水平随着人类的衰老而降低 脑。 因此，具体目标1将确定CBF是否 包括减少皮质聊天在内的退化与 MCI患者的认知障碍。 我们的发现 小组导致了CBF的脆弱性的假设 神经元是由于NGF的结合或运输缺陷而导致的 它的高亲和力信号转导TRKA受体，而TRKA受体又导致 AD中的NGF营养支持受损。 对此建议的支持是 从我们的研究中得出，表明NGF蛋白 免疫反应性及其高亲和力TRKA受体的信息 在CBF神经元内减少，而皮质NGF蛋白是 AD中有所增加。 总之这些观察结果表明 NGF蛋白在皮质中积聚，因为它不是 以正常方式运送到CBF消费者Perikarya 它的营养作用需要发生。 具体目标2-3将 确定NGF运输受损是否也与 老年人与年龄相关的MCI。 这些研究将采用现代 立体学，生物测定，免疫组织化学和原位杂交 程序。 这些调查的结果将有很大 对衰老和MCI的治疗策略以及角色的影响 考虑这些问题时的遗传学。