Early Markers of Alzheimer Disease

阿尔茨海默病的早期标志

• 批准号: 8931478
• 负责人: Susan Resnick
• 金额: $ 93.66万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8931478
• 关键词: Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anterior; Area; Autopsy; Baltimore; Biological Markers; Brain; Cell Nucleolus; Cell Nucleus; Cessation of life; Cleaved cell; Clinical; Cognitive; Cognitive aging; Collaborations; Complement; Data; Dementia; Diagnosis; Disease; Disease Progression; Enrollment; Enzymes; Family; Genetic; Goals; Hippocampus (Brain); Home environment; Hormonal; Hypertrophy; Immediate Recalls; Impaired cognition; Impairment; Individual; Learning; Link; Longitudinal Studies; Measures; Mental Depression; Messenger RNA; Metabolic; Mission; National Institute on Aging; Neurodegenerative Disorders; Neurologic; Neurons; Outcome; Paper; Participant; Pathogenesis; Pathology; Patients; Phase; Process; Production; Prospective Studies; Proteins; Publishing; RNA-Binding Proteins; Reporting; Research; Risk; Risk Factors; Role; Severities; Site; Sorting - Cell Movement; Staging; Superior temporal gyrus; Testing; Time; Tissues; Transcript; Untranslated RNA; Untranslated Regions; aged; area striata; beta-site APP cleaving enzyme 1; cingulate gyrus; cognitive change; depressive symptoms; disorder control; immunoreactivity; meetings; mild cognitive impairment; neuronal cell body; neuropathology; neuropsychological; novel strategies; pre-clinical; prevent; prospective; psychologic; tau Proteins; tau-1

The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to sort out changes due to aging from those due to disease or other causes. Over the last year, we have published a number of papers investigating the effects of possible modifiers of cognitive aging, risk for dementia, and the presence of Alzheimer's pathology at autopsy. In one paper, we applied a new approach using a Disease Progression Scale to investigate domain-specific cognitive trajectories in relation to cognitive impairment. We found that declines in verbal immediate recall were the earliest changes detected but as the underlying disease progressed, verbal delayed recall declines were steeper than those for immediate recall. This finding helps reconcile the observation from prospective studies that changes in immediate recall are evident earliest whereas in clinical settings where impairment is more likely, delayed recall may be more informative. Using data from the BLSA autopsy study, we investigated quantitative measures of amyloid and tau burden in individuals with asymptomatic Alzheimer's disease (ASYMAD) who were clinically normal at death but had sufficient pathology to meet pathological criteria for AD. We previously reported hypertrophy of neuronal cell bodies, nuclei, and nucleoli in the CA1 of the hippocampus (CA1), anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex of ASYMAD versus age-matched Control and mild cognitive impairment (MCI) subjects. However, it was unclear whether the neuronal hypertrophy could be attributed to differences in the severity of AD pathology. Here, we performed quantitative analyses of the severity of Beta-amyloid (ABeta) and phosphorylated tau (tau) loads in the brains of ASYMAD, Control, MCI, and AD subjects (n = 15 per group) from the Baltimore Longitudinal Study of Aging. Tissue sections from CA1, anterior cingulate gyrus, posterior cingulate gyrus, and primary visual cortex were immunostained for ABeta and tau; the respective loads were assessed using unbiased stereology by measuring the fractional areas of immunoreactivity for each protein in each region. The ASYMAD and MCI groups did not differ in ABeta and tau loads. These data confirm that ASYMAD and MCI subjects have comparable loads of insoluble ABeta and tau in regions vulnerable to AD pathology despite divergent cognitive outcomes. These findings imply that cognitive impairment in AD may be caused or modulated by factors other than insoluble forms of ABeta and tau. In a collaborative NIA project, tissue from BLSA autopies was used to investigate the neuronal RNA-binding protein HuD in AD. We reported the identification of several HuD target transcripts linked to Alzheimer's disease (AD) pathogenesis. HuD interacted with the 3' UTRs of APP mRNA (encoding amyloid precursor protein) and BACE1 mRNA (encoding ABeta-site APP-cleaving enzyme 1) and increased the half-lives of these mRNAs. HuD also associated with and stabilized the long noncoding (lnc)RNA BACE1AS, which partly complements BACE1 mRNA and enhances BACE1 expression. Importantly, cortex (superior temporal gyrus) from patients with AD displayed significantly higher levels of HuD and, accordingly, elevated APP, BACE1, BACE1AS, and ABeta than did cortical tissue from healthy age-matched individuals. These findings suggest the possibility that HuD jointly promotes the production of APP and the cleavage of its amyloidogenic fragment, ABeta.

巴尔的摩衰老纵向研究（BLSA）成立于1958年，是美国和世界上最古老的前瞻性研究之一。 BLSA的任务是了解人们变老会发生什么以及如何由于疾病或其他原因导致的变化而解决的变化。 在过去的一年中，我们发表了许多论文，研究了可能的认知衰老，痴呆症风险以及阿尔茨海默氏病在尸检时的存在的影响。 在一篇论文中，我们采用了一种使用疾病进展量表的新方法来研究与认知障碍有关的领域特异性认知轨迹。 我们发现，口头立即召回的下降是检测到的最早的变化，但是随着潜在疾病的进展，口头延迟的召回下降比立即召回的疾病更陡。这一发现有助于调和前瞻性研究的观察结果，即立即召回的变化最早是显而易见的，而在更有可能损害的临床环境中，延迟的召回可能会更有益。 使用BLSA尸检研究中的数据，我们研究了无症状阿尔茨海默氏病（ASYMAD）患者的淀粉样蛋白和TAU负担的定量测量，这些人死亡时在临床上正常但有足够的病理学来满足AD的病理标准。 我们先前报道了海马（CA1）CA1中神经元细胞体，核和核仁的肥大，前扣带回回，后扣带回回和ASYMAD与年龄匹配的对照对照和轻度认知障碍（MCI）受试者的原发性可视皮层。但是，尚不清楚神经元肥大是否可以归因于AD病理严重程度的差异。在这里，我们对β-淀粉样蛋白（ABETA）的严重程度和磷酸化的TAU（TAU）负载进行了定量分析，该载荷是从巴尔的摩纵向衰老的巴尔的摩纵向研究中的不良，对照，MCI和AD受试者（每组n = 15）的大脑中的。从CA1，前扣带回回，后扣带回回和原发性视觉皮层的组织切片被免疫以用于Abeta和Tau。使用公正的立体学评估各自的载荷，通过测量每个区域中每种蛋白质的免疫反应性的分数区域。 ABETA和TAU负载方面的ASYMAD和MCI组没有差异。这些数据证实，尽管认知结果有分歧，但不可溶性和MCI受试者在容易受到AD病理方面的不溶性ABETA和TAU的可比负载。这些发现表明，AD的认知障碍可能是由Abeta和Tau的不溶性形式以外的其他因素引起或调节的。 在一个协作NIA项目中，使用BLSA自动启动的组织用于研究AD中的神经元RNA结合蛋白HUD。 我们报告了与阿尔茨海默氏病（AD）发病机理相关的几个HUD目标转录物的鉴定。 HUD与App mRNA的3'UTR相互作用（编码淀粉样蛋白前体蛋白）和BACE1 mRNA（编码Abeta Site-Site App-Cleaving酶1），并增加了这些mRNA的半衰期。 HUD还与长期非编码（LNC）RNA BACE1AS相关并稳定，这部分与BACE1 mRNA相互补充并增强BACE1表达。重要的是，与来自健康年龄匹配的个体的皮质组织相比，AD患者的皮质（上颞回）的HUD水平明显更高，并且相应地升高了APP，BACE1，BACE1AS和ABETA。这些发现表明，HUD共同促进APP的产生及其淀粉样蛋白生成片段Abeta的裂解的可能性。