Dissecting molecular mechanisms involved in resilience of Alzheimer's pathology

描述（由申请人提供）：从最近的临床-神经病理学相关研究和PET淀粉样蛋白成像研究中可以清楚地看出，阿尔茨海默氏症（AD）病理的发生与认知障碍之间可能存在分离。在Nun研究中，12%的认知完好的受试者在死亡时尸检时发现大量的淀粉样斑块和神经原纤维缠结，符合AD的病理标准（Riley et al, 2005）。来自宗教秩序研究和记忆与衰老项目的最新数据也表明，在没有认知障碍症状的老年人中，约有三分之一的大脑表现出足够的阿尔茨海默病病理，足以满足NIA-Reagan研究所对中度或高可能性阿尔茨海默病的标准（Schneider等人，2009）。与这些观察结果一致，超过20%的临床未受损老年志愿者中PET匹兹堡化合物B （PIB）潴留（纤维A沉积物）升高（Lopresti等人，2005；Mintun等人，2006；Rowe等人，2007;Aizenstein 2008）。综上所述，上述数据表明，尽管在尸检时发现大量淀粉样蛋白和tau蛋白病理，但有些人在活着的时候仍然没有痴呆症的症状。本应用程序的目的是评估两个相互竞争的假设：一些人类大脑是否能抵抗阿尔茨海默病病理（淀粉样斑块和神经原纤维缠结）的损害，在这种情况下，涉及的神经保护机制是什么？还是β /tau的类型（可溶性低聚体β /tau vs纤维淀粉样斑块/神经原纤维缠结）决定了AD的结构损伤和认知功能受损？我们认为，这些阿尔茨海默病的神经病理标准在生活中被发现是非痴呆的病例（我们称之为“不匹配”），尽管不常见，但对于理解为什么有些人对阿尔茨海默病有弹性是很重要的。我们汇集了5个中心的资源，马萨诸塞ADRC，匹兹堡ADRC，梅奥ADRC，华盛顿大学ADRC和哥伦比亚ADRC，他们都在积极研究这个问题，利用大样本量的优势，加速这些重要问题的答案。我们计划结合详细的定量组织病理学和生化评估，重点研究可溶性β和tau蛋白组装和神经胶质激活/炎症在神经元和突触损伤中的作用，以扩展我们对这些病例的生化和分子表征的理解。我们相信这项研究的预期结果有可能显著影响阿尔茨海默病的治疗领域，因为它们可能有助于为老年人的神经保护和认知保留治疗提供合理的方法。

DESCRIPTION (provided by applicant): It is clear from recent clinical-neuropathological correlation studies and PET amyloid imaging studies that there can be a dissociation between the occurrence of Alzheimer's (AD) pathology and cognitive impairment. In the Nun Study, 12% of cognitively intact participants at the time of death had abundant amyloid plaques and neurofibrillary tangles at postmortem exam and met pathological criteria for AD (Riley et al., 2005). Recent data from the Religious Orders Study and the Memory and Aging Project also showed that about one third of brains from older people without symptoms of cognitive impairment demonstrated enough AD pathology to meet NIA-Reagan Institute criteria for intermediate or high likelihood of AD (Schneider et al., 2009). Consistent with these observations, elevated PET Pittsburgh Compound B (PIB) retention (fibrillar A¿ deposits) has been reported in more than 20% of clinically unimpaired elderly volunteers (Lopresti et al., 2005; Mintun et al., 2006; Rowe et al., 2007; Aizenstein 2008). All together the above data suggest that some individuals can remain asymptomatic for dementia while alive despite having substantial amounts of both amyloid and tau pathology at autopsy. The goal of this application is to evaluate two competing hypotheses: are some human brains resistant to the insult of Alzheimer's pathology (amyloid plaques and neurofibrillary tangles), and in this case, what are the neuroprotective mechanisms involved? or is the type of Abeta/tau species (soluble oligomeric Abeta/tau vs. fibrilar amyloid plaques/neurofibrillary tangles) what determines structural damage and impaired cognition in AD? We believe that these cases of AD by neuropathological criteria that were found to be non- demented during life (we refer to them as "mismatches"), although uncommon, are of importance to understand why some individuals are resilient to AD pathology. We have pooled resources from 5 Centers, Massachusetts ADRC, Pittsburgh ADRC, Mayo ADRC, Washington University ADRC and Columbia ADRC, that are each actively studying this problem, to take advantage of a large sample size and accelerate answers to these important questions. We plan to use a combination of detailed quantitative histopathology and biochemical assessments focused on examining the role of soluble Abeta and tau assemblies and glial activation/inflammation in neuronal and synaptic damage to extend our understanding of these cases towards their biochemical and molecular characterization. We believe the expected outcomes of this research have the potential to significantly impact the field of therapeutics in AD as they may contribute to provide a rational approach to neuroprotective and cognitive sparing therapies in the elderly.