SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT

轻度认知障碍的突触变化

• 批准号: 7410039
• 负责人: STEPHEN W SCHEFF
• 金额: $ 26.35万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410039
• 关键词: 4 hydroxynonenal; Accounting; Acrolein; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Area; Autopsy; Bioenergetics; Brain; Chromosome Pairing; Cognitive; Cognitive deficits; Coupling; DLG4 gene; Dementia; Development; Diagnostic; Disease; Evaluation; Event; F2-Isoprostanes; Failure; Growth Associated Protein 43; Hippocampus (Brain); Impaired cognition; Individual; Inferior; Lead; Lesion; Link; Lobule; Memory; Mitochondria; Neocortex; Neurofibrillary Tangles; Numbers; Oxidative Stress; Parietal; Pathogenesis; Pathologic; Performance; Phase; Play; Process; Proteins; Research Personnel; Role; Senile Plaques; Sensory; Severities; Structure of postcentral gyrus; Synapses; Testing; Thinking; Transmission Electron Microscopy; Work; cognitive function; insight; mild neurocognitive impairment; neocortical; neurochemistry; presynaptic density protein 95; sensory cortex; synaptic function

DESCRIPTION (provided by applicant): Mounting evidence suggests that individuals with mild cognitive impairment (MCI) have an increased likelihood to develop Alzheimer's disease (AD). It is unclear what early pathophysiological changes may underlie this transition. The brains of individuals with definite AD manifest several pathological changes including a substantial loss of synapses in association areas of the neocortex. Recent work has now demonstrated that synaptic loss provides an excellent correlation with cognitive ability and provides a strong correlate of dementia. The relationship between synapse loss, early cognitive decline, such as that observed in MCI, is poorly understood. There is increasing evidence that amyloid beta peptide (Abeta) and oxidative damage may be fundamentally involved in the pathogenesis of AD and contribute to MCI. The interaction between Abeta, oxidative damage and synapse loss may provide important keys to the mechanisms that lead to MCI. This proposal will examine the hypothesis that synapse loss is associated with cognitive deficits observed in the early phase of the disease process, and is responsible for amnestic memory problems associated with MCI. Studies will be carried out on short postmortem interval brains from individuals characterized as no cognitive impairment (NCI), MCI, and early AD, and evaluation of total synapses will be obtained by coupling unbiased stereology with transmission electron microscopy. Since Abeta is considered by many researchers to play an important role in progression of AD, we will study the relationship of soluble Abeta1-42 with synaptic loss and pre/post synaptic proteins. The specific aims will also test the hypothesis that oxidative damage is an early indicator of MCI and is associated with changes in total synaptic numbers in neocortical association areas known to be affected early in AD. Finally, we will study possible changes in mitochondrial bioenergetics that occur in MCI and early AD since mitochondria can be affected by both Ap and oxidative stress and are important for synapse function. Successful completion of the proposed studies will lead to new insights into the mechanisms underlying MCI and early AD and contribute to the development of effective pharmacologic therapies for AD.

描述(由申请人提供)：越来越多的证据表明，患有轻度认知障碍(MCI)的人患阿尔茨海默病(AD)的可能性增加。目前尚不清楚这种转变的基础可能是什么早期的病理生理变化。明确患有阿尔茨海默病的人的大脑表现出几种病理变化，包括新皮质相关区域的突触大量丧失。最近的研究表明，突触丢失与认知能力有很好的相关性，也与痴呆症有很强的相关性。突触丢失和早期认知功能下降之间的关系，比如在MCI中观察到的，目前还知之甚少。越来越多的证据表明，淀粉样β蛋白(Abeta)和氧化损伤可能从根本上参与了AD的发病机制，并有助于MCI的发生。Abeta、氧化损伤和突触丢失之间的相互作用可能为MCI的机制提供重要的关键。这项建议将检验突触丢失与疾病过程早期观察到的认知缺陷有关的假设，并对与MCI相关的遗忘性记忆问题负责。研究将在没有认知损害(NCI)、MCI和早期AD的个体的短死后间隔脑中进行，并将通过无偏向体视学和透射电子显微镜相结合的方法获得对总突触的评估。鉴于许多研究人员认为Abeta1-42在AD的进展中起重要作用，我们将研究可溶性Abeta1-42与突触丢失和突触前/后蛋白的关系。特定的目标还将检验氧化损伤是MCI的早期指标，并与已知在AD早期受到影响的新皮质关联区中突触总数的变化有关的假设。最后，我们将研究线粒体生物能量学在MCI和早期AD中可能发生的变化，因为线粒体可以同时受到AP和氧化应激的影响，并且对突触功能非常重要。这项拟议研究的成功完成将为MCI和早期AD的机制带来新的见解，并有助于开发有效的AD药物治疗方法。