SYNAPTIC CHANGE IN MILD COGNITIVE IMPAIRMENT

轻度认知障碍的突触变化

• 批准号: 7150089
• 负责人: STEPHEN W SCHEFF
• 金额: $ 27.69万
• 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/7150089
• 关键词: Alzheimer' s disease; amyloid proteins; bioenergetics; biomarker; clinical research; cognition disorders; disease /disorder proneness /risk; human tissue; membrane proteins; memory disorders; mitochondria; neocortex; neural degeneration; neural growth associated protein; neuropathology; oxidative stress; pathologic process; postmortem; protein protein interaction; sensory cortex; synapses; transmission electron microscopy

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背后可能存在哪些早期病理生理变化。患有明确 AD 的个体的大脑表现出多种病理变化，包括新皮质关联区域突触的大量损失。最近的研究表明，突触损失与认知能力具有极好的相关性，并且与痴呆症具有很强的相关性。突触丧失与早期认知能力下降（如 MCI 中观察到的情况）之间的关系尚不清楚。越来越多的证据表明，β 淀粉样肽 (Abeta) 和氧化损伤可能从根本上参与 AD 的发病机制，并导致 MCI。 Abeta、氧化损伤和突触损失之间的相互作用可能为导致 MCI 的机制提供重要的关键。该提案将检验这样的假设：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 相关的遗忘性记忆问题。将对无认知障碍 (NCI)、MCI 和早期 AD 个体的短期死后大脑进行研究，并通过将无偏见的体视学与透射电子显微镜相结合来评估总突触。由于许多研究人员认为 Abeta 在 AD 进展中发挥重要作用，因此我们将研究可溶性 Abeta1-42 与突触损失和突触前/后蛋白的关系。具体目标还将检验氧化损伤是 MCI 的早期指标并与已知在 AD 早期受影响的新皮质关联区域总突触数量变化相关的假设。最后，我们将研究 MCI 和早期 AD 中发生的线粒体生物能学可能发生的变化，因为线粒体可能受到 Ap 和氧化应激的影响，并且对突触功能很重要。拟议研究的成功完成将为 MCI 和早期 AD 的机制提供新的见解，并有助于开发有效的 AD 药物疗法。