FOREBRAIN NEUROTROPIC ABNORMALITIES & MILD COGNITIVE IMPAIRMENT IN THE ELDERLY

前脑神经营养异常

• 批准号: 6299385
• 负责人: ELLIOTT Jay MUFSON
• 金额: $ 17.62万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299385
• 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 从轻微的异常到明显的痴呆，分子和 解释这种变异的细胞底物仍有待定义。 一些报告表明，老年人的胆碱能功能低下。 然而，这些研究中没有一项与胆碱能变化与认知有关。 状态。这个系统对人类认知的重要性是 阿尔茨海默病(AD)的研究强调了这一点，在那里 持续的神经化学异常与认知能力有关 损害是皮质胆碱乙酰转移酶(ChAT)的减少。 有趣的是，AD患者的基因剂量增加 载脂蛋白(ApoE)e4等位基因(AD的遗传危险因素) 更大的胆碱能缺陷(即皮质ChAT减少和 胆碱能基底前脑(CBF)神经元丢失)，反应较差 到抗胆碱酯酶药物。CBF系统的现状和 老年轻症患者载脂蛋白E基因多态性的相关性研究 然而，认知障碍(MCI)仍不清楚。我们确实知道， 然而，人类大脑皮质聊天水平随着年龄的增长而降低 大脑。因此，具体目标1将确定CBF是否 包括皮质聊天减少在内的认知障碍与 MCI患者的认知功能障碍。来自我们的调查结果 导致了CBF的脆弱性的假说 神经元是由于NGF结合或运输存在缺陷而产生的 它的高亲和力信号转导TrkA受体，进而导致 AD患者NGF营养支持受损。对这一建议的支持是 来源于我们的研究表明，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 在AD中增加。综上所述，这些观察表明 NGF蛋白在皮质内积聚，因为它不是 以正常方式运送到CBF消费者佩尔卡里亚 需要它的营养作用才能发生。具体目标2-3将 确定NGF转运受损是否也与 老年人的年龄相关性MCI。这些研究将使用现代化的 体视学、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重大的 老龄化和MCI治疗策略的意义及其作用 遗传学在考虑这些问题时的作用。