SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT

轻度认知障碍的突触变化

基本信息

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
项目类别：
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&apos 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

项目摘要

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）的个体发展了发展阿尔茨海默氏病（AD）的可能性增加。目前尚不清楚哪些早期的病理生理变化可能是这种过渡的基础。具有明确AD的个体的大脑表现出了几种病理变化，包括新皮层关联区域中突触的大量丧失。最近的工作现在表明，突触损失与认知能力有着良好的相关性，并提供了痴呆症的牢固相关性。突触流失，早期认知下降（例如MCI中观察到的）之间的关系知之甚少。有越来越多的证据表明，淀粉样蛋白β肽（ABETA）和氧化损伤可能与AD发病机理有根本性地涉及并有助于MCI。 ABETA，氧化损伤和突触损失之间的相互作用可能为导致MCI的机制提供重要的密钥。该提案将检验以下假设：突触丧失与疾病过程早期观察到的认知缺陷有关，并导致与MCI相关的敏感记忆问题。研究将在较短的验化后间隔大脑中进行，该个体的个人表征为无认知障碍（NCI），MCI和早期AD，并通过将无偏的立体学与透射电子显微镜偶联来获得总突触的评估。由于许多研究人员认为ABETA在AD的发展中发挥重要作用，因此我们将研究可溶性Abeta1-42与突触损失和突触前/突触后蛋白的关系。具体目的还将检验以下假设：氧化损伤是MCI的早期指标，并且与已知在AD早期受到影响的新皮层关联区域的总突触数变化有关。最后，我们将研究MCI和AD中发生的线粒体生物能学的可能变化，因为线粒体可能受AP和氧化应激的影响，对突触功能很重要。成功完成拟议的研究将导致对MCI和早期AD基础机制的新见解，并有助于开发有效的AD药理疗法。