Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

将睡眠功能障碍与 AD 进展过程中 Tau 蛋白相关的退化联系起来

• 批准号: 10328419
• 负责人: Lea Tenenholz Grinberg
• 金额: $ 1.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328419
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid beta-Protein; Animals; Area; Arousal; Autopsy; Award; Behavior; Biological Models; Brain; Brain region; Cell Nucleus; Circadian Dysregulation; Circadian Rhythms; Clinical; Complement; Disease Progression; Etiology; Experimental Models; Human; Impaired cognition; Institutionalization; Link; Longitudinal cohort; Measures; Methods; Modeling; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Parents; Patients; Pattern; Population; Positron-Emission Tomography; Regulation; Role; Senile Plaques; Sleep; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Suggestion; Tauopathies; Testing; Tissue Banks; abeta deposition; aged; base; brain cell; circadian; cohort; experience; human model; non rapid eye movement; novel; programs; protein aggregation; sleep regulation; tau Proteins; tau-1

PROJECT SUMMARY / ABSTRACT (from parent award) Sleep and circadian disturbances occur often and even precede the onset of cognitive decline, in Alzheimer' disease (AD) and other neurodegenerative diseases – and constitute a common reason for institutionalization. Sleep loss, particulary slow wave sleep (SWS), and sleep fragmentation, may contribute causally to AD by increasing amyloid-beta (Aβ) deposition, as described in PAR-18-497, but Aβ alone appears insufficient to explain all mechanisms and causation of AD clinical manifestations and disordered sleep. We discovered converging evidence in human sleep and neuropathological studies suggestive of a primary, novel role of tauopathy in AD-disordered sleep. In this connection, in postmortem brains of AD subjects, subcortical nuclei involved in circandian-sleep- -wake regulation are among the first to develop AD-type tau-based neurofibrillary tangles, before Aβ plaques appear. Our working hypothesis is that tau-induced degeneration of subcortical nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing is an early contributor to disrupted sleep- wake behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep disturbance and accelerated Aβ deposition. We propose to test if differences in sleep-wake behavior in progressive AD stages versus healthy controls vs. PSP ( a pure tauopathy more pronounced in subcortical areas) are accounted by differences in quantitative pathoanatomical measures (including numbers of total and specific neuronal population, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation. We are uniquely poised to suceed due to our access to large longitudinal cohorts of AD and PSP patients and similarly-aged controls and successful autopsy program, expertise in p-tau and Aβ PET imaging, deep experience in clinical sleep studies in neurodegenerative disorders, tissue collections of aged controls, cases encompassing all-AD spectrum and other tauopathies, enabling stereology of whole brain regions, experience in human subcortical pathoanatomy, and cutting-edge neuropathological methods and brain network approach. This combination of factors create a unique opportunity to exploit novel human findings that will inform and complement mechanistic hypotheses and testing in model systems. This is critical, because animals' sleep- wake patterns and AD-like models diverge from those of humans and experimental models rather mimic non- AD tauopathies than tau-related AD patterns. We anticipate our findings will inform critical information on the temporal sequence of disrupted sleep and/or circadian rhythms and the accumulation and spreading of protein aggregates such as p-t and Aβ in AD. Beyond this, results from this study will inform rational therapies for treating disturbed sleep in AD.

项目摘要/摘要（来自家长奖）