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.

虽然老年人（>65岁）表现出认知障碍， 从轻微的异常到明显的痴呆， 解释这种变化的细胞基质仍有待确定。 一些报告表明老年人胆碱能功能减退。 然而，这些研究都没有将胆碱能变化与认知功能 status. 这个系统对人类认知的重要性在于 阿尔茨海默病（AD）的研究强调， 一致的神经化学异常与认知 损伤是皮质胆碱乙酰转移酶（ChAT）降低。 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）表现出 更大的胆碱能缺陷（即，皮质ChAT减少， 胆碱能基底前脑（CBF）神经元损失）并且响应性较低 抗胆碱酯酶药物。 CBF系统的现状和 老年人ApoE基因型与轻度脑梗死的相关性 然而，认知障碍（MCI）仍然是未知的。 我们知道， 然而，在人类中，皮质ChAT水平随着年龄增长而降低 个脑袋 因此，具体目标1将确定CBF是否 包括皮质ChAT减少在内的退化与 MCI患者的认知障碍。 我们的调查结果 小组，导致了假设，CBF的脆弱性 神经元是由于NGF的结合或运输缺陷而产生的， 它的高亲和力信号转导trkA受体，反过来，导致 AD中受损的NGF营养支持。 支持这一建议的是 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增加。 这些观察结果表明， 神经生长因子蛋白质在大脑皮层内积累， 以正常方式运输到CBF消费者perikarya， 产生营养效应所必需的。 具体目标2-3将 确定受损的NGF运输是否也与 与年龄相关的MCI。 这些研究将采用现代 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影响。 对衰老和MCI治疗策略的影响以及 遗传学在考虑这些问题。