SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT

轻度认知障碍的突触变化

• 批准号: 7617169
• 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/7617169
• 关键词: 4 hydroxynonenal; Accounting; Acrolein; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Area; Autopsy; Bioenergetics; Brain; Cognitive; Cognitive deficits; Coupling; 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; Oxidative Stress; Parietal; Pathogenesis; Pathologic; Performance; Phase; Play; Process; Proteins; Research Personnel; Role; Senile Plaques; Sensory; Severities; Structure of postcentral gyrus; Synapses; Testing; Transmission Electron Microscopy; Work; cognitive function; insight; mild neurocognitive impairment; neocortical; neurochemistry; oxidative damage; 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，轻度认知障碍（MCI）的个体患阿尔茨海默病（AD）的可能性增加。目前还不清楚这种转变的基础是什么早期病理生理变化。患有明确AD的个体的大脑表现出几种病理变化，包括新皮层的关联区域中的突触的大量丧失。最近的研究表明，突触丧失与认知能力有很好的相关性，并与痴呆有很强的相关性。突触丢失和早期认知能力下降之间的关系，如在MCI中观察到的，知之甚少。越来越多的证据表明，淀粉样β肽（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。Abeta、氧化损伤和突触丢失之间的相互作用可能为导致MCI的机制提供重要的关键。该提案将检验突触丧失与在疾病过程的早期阶段观察到的认知缺陷相关的假设，并且是与MCI相关的遗忘记忆问题的原因。研究将对无认知障碍（NCI）、MCI和早期AD个体的短死后间隔脑进行，并通过无偏体视学与透射电子显微镜结合来评估总突触。由于Abeta被许多研究者认为在AD的进展中起重要作用，因此我们将研究可溶性Abeta 1 -42与突触丢失和突触前/后蛋白的关系。具体的目标也将测试的假设，即氧化损伤是MCI的早期指标，并与已知在AD早期受影响的新皮质关联区的总突触数量的变化。最后，我们将研究在MCI和早期AD中发生的线粒体生物能量学的可能变化，因为线粒体可以受到Ap和氧化应激的影响，并且对突触功能很重要。成功完成拟议的研究将导致新的见解MCI和早期AD的机制，并有助于开发有效的药物治疗AD。