Beta-amyloid peptides in the oldest-old: A biochemical profile of successful agin

描述（由申请人提供）：阿尔茨海默氏病（AD）所带来的问题越来越多，而治愈或可靠的症状缓解都是遥不可及的。大量证据表明淀粉样蛋白在AD病理学中起着关键作用，但最近的淀粉样蛋白（A）免疫疗法的人体试验表明痴呆症不仅仅涉及老年斑的积累。俄勒冈州的脑老化研究（OBAS）揭示了存在一个最老的老年群体（>85岁），他们成功地保持了认知能力到老年。仅根据组织学判断，这些非痴呆的最年长个体中的一些表现出足以导致AD诊断的脑病理学，但仍保留未减弱的精神能力。这些具有广泛特征的最年长的OBAS参与者提供了一个非凡的机会，可以比较和对比认知成功的老年人与年龄匹配的痴呆症患者的A？概况。利用方法来分离和表征可溶性以及所有沉积形式的A？在脑实质和血管系统，包括膜内的物种，我们将比较详细的A？分子谱的神经病理学评估，非痴呆最老的老年组中存在的AD患者痴呆。质谱分析将使我们能够编制非痴呆受试者、表现出典型AD病变的非痴呆受试者（高病理对照）和痴呆AD患者中存在的A？谱的深入名册。淀粉样蛋白前体蛋白质的蛋白水解模式将通过蛋白质印迹实验来检测，以揭示与AD病例相比，在非痴呆老年人中淀粉样蛋白生成加工途径是否被较少程度地使用或完全被使用。淀粉样蛋白破坏疗法已显示出巨大的前景。理解A？表现出最大毒性的物种或与痴呆症最相关的特征提供了更精确的治疗干预的前景，这些干预既消除了病理，又保留了认知能力。 公共卫生相关性： 最近的阿尔茨海默病（AD）疗法的临床试验既令人鼓舞又令人失望，因为发现虽然老年性淀粉样蛋白斑块沉积物被去除，但仅凭此不能治愈痴呆症。利用一项系统研究那些在老年时仍保持认知能力的最年长者的计划，我们将评估这些人如何在成功避免痴呆症的同时管理淀粉样蛋白的产生和周转。这项工作将有助于澄清哪些淀粉样蛋白种类或积累模式与痴呆症最相关，并有助于设计更精确的靶向治疗方法来阻止AD的出现。

DESCRIPTION (provided by applicant): The problems posed by Alzheimer's disease (AD) mount while neither a cure nor reliable relief from symptoms lies within reach. Substantial evidence reveals amyloid plays a key role(s) in AD pathology, but recent human trials of amyloid-¿ (A¿) immunotherapy suggest dementia involves more than senile plaque accumulation. The Oregon Brain Aging Study (OBAS) has revealed the existence of an oldest-old cohort (>85 years of age) who successfully maintain cognitive capabilities into advanced ages. Judged solely on histology, some of these non-demented oldest- old individuals exhibited brain pathology sufficient to result in an AD diagnosis, yet still retained undiminished mental abilities. These extensively characterized oldest-old OBAS participants present an extraordinary opportunity to compare and contrast the A¿ profiles of the cognitively successful elderly to those of age-matched demented cases. Utilizing methods to isolate and characterize soluble as well as all deposited forms of A¿ within the brain parenchyma and vasculature, including intra-membranous species, we will compare the detailed A¿ molecular profiles of neuropathologically-assessed, non-demented oldest-old groups to those present in AD patients with dementia. Mass spectrometry analyses will enable us to compile in-depth rosters of the A¿ spectrum existing within non-demented subjects, non-demented subjects exhibiting classic AD lesions (high pathology controls) and demented AD patients. Amyloid-¿ precursor protein proteolysis patterns will be examined by Western blot experiments to reveal if amyloidogenic processing pathways are used to a lesser extent or employed at all in the non-demented aged compared to AD cases. Amyloid disruption therapy has shown great promise. Understanding which A¿ species exhibit the greatest toxicity or the profiles most associated with dementia offers the prospect of more precise therapeutic interventions that both eliminate pathology while preserving cognitive capacity. PUBLIC HEALTH RELEVANCE: Recent clinical trials of Alzheimer's Disease (AD) therapies have been both encouraging and disappointing due to the discovery that while senile amyloid plaque deposits are removed, this alone is not able to cure dementia. Taking advantage of a program that systematically studies the oldest-old individuals who retain cognitive capacity to advanced ages, we will assess how these persons manage amyloid production and turnover while successfully avoiding dementia. This work will help to clarify which amyloid species or accumulation patterns are most associated with dementia and help to devise more precisely targeted therapies to stop AD emergence.