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

最古老的β-淀粉样肽：成功的 agin 的生化特征

• 批准号: 7772431
• 负责人: ALEX E ROHER
• 金额: $ 22.06万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772431
• 关键词: Age; Age-Years; Aged, 80 and over; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Benign; Binding; Biochemical; Biochemistry; Blood Vessels; Brain; Brain Pathology; Cerebral cortex; Cessation of life; Characteristics; Chemicals; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Data; Defense Mechanisms; Dementia; Deposition; Diffuse; Disease; Elderly; Enrollment; Enzymes; Excision; Exhibits; Filament; Health; Histology; Human; Immunotherapy; Individual; Insulinase; Knowledge; Lesion; Mass Spectrum Analysis; Membrane; Methods; Modeling; Molecular Profiling; Neprilysin; Neurologic; Oregon; Participant; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Patients; Pattern; Peptides; Persons; Pharmaceutical Preparations; Play; Population; Process; Production; Protein Precursors; Proteolysis; Psyche structure; Psychometrics; Recording of previous events; Research; Resources; Role; Senile Plaques; Source; Staging; Symptoms; Testing; Therapeutic Intervention; Time; Toxic effect; Vaccinated; Water; Western Blotting; Work; aged; aging brain; base; brain tissue; case control; cohort; comparative; disease diagnosis; gray matter; neuropathology; programs; public health relevance; research study

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.

描述（由适用提供）：阿尔茨海默氏病（AD）坐骑带来的问题，而症状也不可靠地缓解症状。大量证据表明，淀粉样蛋白在AD病理学中起着关键作用，但是最近对淀粉样蛋白的人类免疫疗法的人类试验表明，痴呆症比老年斑块积累更多。俄勒冈州脑老化研究（OBAS）揭示了一个最古老的队列（> 85岁），他们成功地将认知能力保持在高级时代。仅根据组织学来判断，其中一些非痴呆的最古老的人暴露了足以导致AD诊断的脑病理学，但仍保留了未限制的心理能力。这些广泛的特征是最古老的OBAS参与者提供了一个非凡的机会，可以将认知成功与年龄匹配的痴呆症病例的认知成功率进行比较和对比。利用方法隔离和表征固体以及在脑实质和脉管系统中的所有沉积形式，包括植物内物种，我们将比较神经病理学评估，未痴呆的，未痴呆的老年人的详细A分子特​​征与在痴呆症患者中存在的那些。质谱分析将使我们能够编译非痴呆受试者中现有的A频谱的深入阵列，非痴呆的受试者表现出经典的AD病变（高病理控制）和痴呆的AD患者。淀粉样蛋白蛋白蛋白蛋白蛋白水解模式将通过蛋白质印迹实验检查，以揭示与AD病例相比，淀粉样蛋白生成的加工途径是在较小程度上使用的淀粉样蛋白生成途径。淀粉样蛋白破坏疗法表现出了很大的希望。了解哪种物种表现出最大的毒性或与痴呆症最相关的特征提供了更精确的治疗干预措施，这些干预措施既消除了病理学，又可以保留认知能力。 公共卫生相关性：最近的阿尔茨海默氏病（AD）疗法的临床试验既令人鼓舞又令人失望。利用一个计划，该计划系统地研究了将认知能力保留到高级年龄的最古老的人，我们将评估这些人如何管理淀粉样蛋白的生产和营业额，同时成功避免痴呆症。这项工作将有助于阐明哪些淀粉样物种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以阻止AD出现。