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

描述(申请人提供)：阿尔茨海默病(AD)带来的问题越来越多，而治疗或可靠的缓解症状是遥不可及的。大量证据表明，淀粉样蛋白在AD病理中起着关键作用(S)，但最近人类对淀粉样蛋白免疫疗法的试验表明，痴呆症涉及的不仅仅是老年斑的堆积。俄勒冈州大脑老化研究(OBAS)揭示了一组年龄最大的人(85岁)，他们成功地将认知能力保持到了高龄。仅从组织学来判断，这些非痴呆的老年个体中的一些人表现出足以导致AD诊断的大脑病理，但仍然保持着不受影响的智力。这些被广泛描述为年龄最大的OBA参与者提供了一个非同寻常的机会，可以比较和对比认知成功的老年人和年龄匹配的痴呆症患者的A？概况。利用分离和表征脑实质和血管系统中的所有可溶和沉积形式的A？，包括膜内物种的方法，我们将比较神经病理评估的、非痴呆的最老老年组与AD痴呆患者中存在的A？的详细分子图谱。质谱仪分析将使我们能够编辑非痴呆受试者、表现典型AD病变(高度病理对照)的非痴呆者和痴呆性AD患者中存在的A？谱的深入花名册。淀粉样前体蛋白的蛋白分解模式将通过Western印迹实验进行检测，以揭示与AD病例相比，非痴呆老年人是否较少地使用或根本使用了淀粉样蛋白生成的处理途径。淀粉样蛋白干扰疗法已经显示出巨大的前景。了解哪些物种表现出最大的毒性或与痴呆症最相关的特征，为更精确的治疗干预提供了前景，既消除了病理，又保留了认知能力。 与公共卫生相关：最近阿尔茨海默病(AD)疗法的临床试验既令人鼓舞，也令人失望，因为发现虽然老年性淀粉样斑块沉积被移除，但仅有这一点并不能治愈痴呆症。利用一个系统研究保持认知能力到高龄的最年长老年人的计划，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疗法来阻止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.