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 造成这种变化的细胞底物仍有待定义。 一些报告表明老年人胆碱能功能减退。 然而，这些研究均未将胆碱能变化与认知能力联系起来。 地位。 该系统对人类认知的重要性在于 阿尔茨海默病 (AD) 的研究强调了这一点： 与认知相关的一致的神经化学异常 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 的遗传风险因素） 更大的胆碱能缺陷（即皮质 ChAT 减少和 胆碱能基底前脑（CBF）神经元损失）并且反应较弱 抗胆碱酯酶药物。 CBF系统的现状和 ApoE 基因型与轻度老年个体的关联 然而，认知障碍（MCI）仍然未知。 我们确实知道， 然而，皮质 ChAT 水平随着人类衰老而降低 脑。 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 组，导致了这样的假设：CBF 的脆弱性 神经元是由 NGF 的结合或运输缺陷引起的 其高亲和力信号转导 trkA 受体，进而导致 AD 中 NGF 营养支持受损。 对这个建议的支持是 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 CBF 神经元内的 NGF 蛋白减少，而皮质 NGF 蛋白则减少 AD 中增加。 综合这些观察结果表明 NGF 蛋白在皮质内积聚，因为它不 以正常方式运输至 CBF 消费者 perikarya 所在位置 其营养作用发生所需。 具体目标 2-3 将 确定 NGF 运输受损是否也与 老年人中与年龄相关的 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。 这些调查结果将产生重大影响 对衰老和 MCI 治疗策略的影响及其作用 遗传学在考虑这些问题时。