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

描述（由申请人提供）：阿尔茨海默病（AD）带来的问题越来越多，而既不能治愈也不能可靠地缓解症状。大量证据表明淀粉样蛋白在阿尔茨海默病病理中起着关键作用，但最近淀粉样蛋白- a免疫疗法的人体试验表明，痴呆症不仅仅涉及老年斑积累。俄勒冈脑老化研究（OBAS）揭示了一个最老的队列（bb0 - 85岁）的存在，他们成功地保持认知能力进入老年。仅从组织学上判断，这些未患痴呆的老年人中的一些人表现出足以导致阿尔茨海默病诊断的脑部病理，但仍保持未减弱的智力能力。这些广泛表征的最年长的OBAS参与者提供了一个非凡的机会来比较和对比认知成功的老年人与年龄匹配的痴呆病例的A¿profiles。利用分离和表征脑薄壁和脉管系统（包括膜内物种）内可溶性和所有沉积形式的A¿的方法，我们将比较神经病理学评估的非痴呆最老组与AD患者痴呆中存在的A¿分子特征。质谱分析将使我们能够在非痴呆受试者、表现出典型AD病变（高病理对照）的非痴呆受试者和痴呆AD患者中编制深入的A¿谱名册。淀粉样蛋白-前体蛋白蛋白水解模式将通过Western blot实验来检测，以揭示与AD病例相比，非痴呆老年人中淀粉样蛋白生成加工途径的使用程度是否较低或根本没有使用。淀粉样蛋白破坏疗法显示出巨大的前景。了解哪些A¿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，既能消除病理，又能保持认知能力。

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.