Mechanisms of resistance to cognitive decline in AD

AD 认知能力下降的抵抗机制

• 批准号: 8728098
• 负责人: Giulio Taglialatela
• 金额: $ 31万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728098
• 关键词: Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Automobile Driving; Behavior; Binding; Biological Preservation; Brain; Caring; Clinical; Cognitive; Competence; Coupled; Deposition; Detection; Development; Docking; Electron Microscopy; Electrophoresis; Elements; Equipment and supply inventories; Event; Fostering; Foundations; Goals; Hand; Health; Health Care Costs; Hippocampus (Brain); Histopathology; Human; Immunohistochemistry; Impaired cognition; Individual; Insulin Resistance; Knowledge; Lead; Lesion; Link; Memory; Mission; Molecular; Molecular Profiling; Mus; Neurofibrillary Tangles; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Patients; Performance; Phosphorylation; Post-Translational Protein Processing; Prevention; Proteins; Proteome; Proteomics; Public Health; Qualifying; Research; Resistance; Risk Factors; Signal Transduction; Social Welfare; Solid; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Synapses; Testing; Toxic effect; Vertebral column; Western Blotting; aging population; behavior test; brain tissue; cost; density; effective therapy; hyperphosphorylated tau; improved; innovation; insulin sensitivity; insulin sensitizing drugs; insulin signaling; interdisciplinary approach; mouse model; neurodegenerative dementia; neuropathology; neurotoxic; public health relevance; resistance mechanism; synaptic function; tau Proteins

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most severe neurodegenerative dementia for which there is currently no cure. Abundant deposition of amyloid beta (A¿) plaques and the presence of neurofibrillary tangles of hyper-phosphorylated tau protein are the two CNS lesions that, concomitant with synaptic disruption and preponderant insulin resistance, hallmark the onset and progression of AD. Some individuals, however, remain cognitively intact despite the presence of substantial AD neuropathology. The existence of these unusual cases (which we termed Non-Demented with Alzheimer's Neuropathology, NDAN) reveals that there is a natural way for the human brain to resist the neurotoxic events that normally lead to cognitive demise in AD. It follows that understanding the molecular mechanisms involved in such resistance would reveal a very effective target for treatment of cognitive decline in AD. Achieving this knowledge is the overarching goal of our research. We present compelling preliminary results supporting the hypothesis that NDAN individuals remain cognitively intact because A¿ oligomers do not bind to, and therefore, do not disrupt post-synaptic elements owing to increased insulin sensitivity that impacts the make-up of the PSD proteome rendering A¿ oligomer docking unlikely. The goal of this application is to establish that, as compared to demented AD, cognitive integrity of NDAN cases is collectively marked by a) molecular evidence of synaptic integrity; b) absence of A¿ oligomers from post-synaptic elements; c) increased insulin sensitivity; d) unique PSD proteome signature. We will test this hypothesis by pursuing the following three specific aims: 1) To demonstrate the presence (or absence) of A¿ oligomers at synapses in the hippocampus and cortex of AD and NDAN brains as a function of synaptic welfare, insulin sensitivity and cognitive competence; 2) To determine the existence of a causal link between sustained insulin signaling and the ability of synapses to reject the disfunctional binding of A¿ oligomers; 3) To determine and contrast the protein make-up of the PSD in control, AD and NDAN cases and in wt mice treated with the insulin sensitizing drug PTZ. Results will characterize the NDAN human synapse which is capable of escaping disruptive targeting by A¿ oligomers and maintaining increased insulin sensitivity and establish a molecular signature underscoring a causal relationship between sustained insulin signaling and the ability of synapses to reject detrimental A¿ oligomer binding. This new knowledge is necessary to lay solid foundations for the identification of potential pharmacological targets for the development of new, effective treatments for AD. We propose a multidisciplinary approach that brings together a uniquely qualified team of experts in neuronal molecular signaling in AD (Taglialatela), CNS electron microscopy (Carlton), behavior in APP Tg mouse models (Dineley), proteomics (Wiktorowicz), AD histopathology (Woltjer) and AD clinical aspects (Quinn).

描述（由适用提供）：阿尔茨海默氏病（AD）是目前无法治愈的最严重的神经退行性痴呆。淀粉样蛋白的大量沉积（A a。）以及高磷酸化的Tau蛋白的神经原纤维缠结是两个CNS病变，与合成破坏和胰岛素胰岛素抵抗相关，标志性地标志着AD和进展。但是，一些人仍然是认知完整的欲望，存在着大量的AD神经病理学。这些不寻常的病例的存在（我们称为阿尔茨海默氏症神经病理学，ndan）表明，人脑有一种自然的方法可以抵抗通常导致AD认知灭亡的神经毒性事件。因此，了解这种抗性所涉及的分子机制将显示出非常有效的AD认知能力下降的靶标。实现这一知识是我们研究的总体目标。我们提出了引人注目的初步结果，支持了NDAN个体保持认知完整的假设，因为A寡聚物与胰岛素敏感性增加，因此不会破坏突触后元素，从而影响PSD Proteome的组成，使PSD Proteome构成无效。该应用的目的是确定，与痴呆的AD相比，NDAN病例的认知完整性统称为A）突触完整性的分子证据。 b）缺乏后突触元素的寡聚物； c）提高胰岛素敏感性； d）独特的PSD蛋白质组签名。我们将通过追求以下三个特定目的来检验这一假设：1）在AD和Ndan Brains的海马和皮质中，在突触中证明A poligomers的存在（或不存在）是突触福利，胰岛素敏感性和认知能力的函数； 2）确定持续的胰岛素信号传导与突触能力拒绝A寡聚物的失功能结合的能力之间存在因果关系； 3）确定和对比对照，AD和NDAN病例以及用胰岛素敏化药物PTZ处理的WT小鼠中PSD的蛋白质组成。结果将表征NDAN人类突触，该突触能够通过A寡聚体逃避破坏性靶向，并保持胰岛素敏感性的提高，并建立分子特征，强调持续的胰岛素信号传导与突触能力之间的因果关系，而突触的能力拒绝有害A？寡聚物的寡聚结合。这种新知识是为了鉴定潜在的药物靶标，以开发新的有效治疗AD的潜在药物目标。 We propose a multidisciplinary approach that brings together a uniquely qualified team of experts in neuronal molecular signaling in AD (Taglialatela), CNS electron microscopy (Carlton), behavior in APP Tg mouse models (Dineley), proteomics (Wiktorowicz), AD histopathology (Woltjer) and AD clinical aspects (Quinn).