SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT

轻度认知障碍的突触变化

• 批准号: 7268814
• 负责人: STEPHEN W SCHEFF
• 金额: $ 26.89万
• 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/7268814
• 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）的个体发展为阿尔茨海默病（AD）的可能性增加。目前尚不清楚是什么早期病理生理变化导致了这种转变。阿尔茨海默氏症患者的大脑表现出几种病理变化，包括新皮层关联区突触的大量丧失。最近的研究表明，突触丧失与认知能力有很好的相关性，与痴呆也有很强的相关性。突触丧失与早期认知能力下降之间的关系，如在轻度认知损伤中观察到的，目前尚不清楚。越来越多的证据表明，淀粉样蛋白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的发生。β，氧化损伤和突触丢失之间的相互作用可能为导致MCI的机制提供了重要的关键。该提案将检验突触丧失与疾病早期阶段观察到的认知缺陷相关的假设，并负责与MCI相关的遗忘记忆问题。研究将对无认知障碍（NCI）、轻度认知障碍（MCI）和早期AD患者的短死后脑进行研究，并通过无偏立体学与透射电子显微镜相结合来评估总突触。由于许多研究者认为Abeta在AD的进展中起着重要作用，我们将研究可溶性Abeta -42与突触丢失和突触前/突触后蛋白的关系。具体目标还将验证氧化损伤是MCI早期指标的假设，并且与已知在阿尔茨海默病早期受影响的新皮质关联区总突触数量的变化有关。最后，我们将研究MCI和早期AD中线粒体生物能量学可能发生的变化，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。这些研究的成功完成将为MCI和早期AD的潜在机制提供新的见解，并有助于开发有效的AD药物治疗方法。