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

基本信息

项目摘要

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.
项目概要/摘要(来自母公司合同) 睡眠和昼夜节律紊乱经常发生,甚至在阿尔茨海默病患者认知能力下降之前发生。 疾病(AD)和其他神经退行性疾病-并构成了机构化的常见原因。 睡眠丧失,特别是慢波睡眠(SWS)和睡眠碎片,可能通过以下方式导致AD 增加淀粉样蛋白β(Aβ)沉积,如PAR-18-497中所述,但单独的Aβ似乎不足以 解释AD临床表现和睡眠障碍的所有机制和原因。我们发现 在人类睡眠和神经病理学研究中的证据表明, AD睡眠障碍中的tau蛋白病在这方面,在AD受试者的死后大脑中,皮质下核团 参与循环睡眠-觉醒调节的人是最早开发AD型tau神经元的人之一。 在Aβ斑块出现之前缠结。我们的假设是tau蛋白诱导的皮质下变性 控制1)SWS; 2)唤醒-觉醒;和3)昼夜节律定时的核团是睡眠中断的早期贡献者- AD患者的觉醒行为,先于认知下降和随后出现的前馈睡眠周期 干扰和加速Aβ沉积。我们建议测试,如果睡眠-觉醒行为的差异, 进行性AD分期与健康对照相比与PSP(一种在皮质下更明显的纯tau蛋白病) 面积)的差异进行了解释定量病理解剖措施(包括总数和 特定的神经元群体和hp-tau负荷)。 由于我们能够获得大量的AD和PSP患者纵向队列, 年龄相似的对照组和成功的尸检计划,p-tau和Aβ PET成像的专业知识, 神经退行性疾病的临床睡眠研究经验,老年对照的组织收集,病例 包括所有AD谱和其他tau蛋白病,使全脑区域的体视学,经验 在人类皮层下病理解剖学、神经病理学方法和脑网络方法等方面的前沿研究。 这些因素的结合创造了一个独特的机会,利用新的人类发现, 补充模型系统中的机械假设和测试。这很关键,因为动物的睡眠- 唤醒模式和AD样模型与人类和实验模型不同,而不是模仿非 AD tau蛋白病变多于tau蛋白相关的AD模式。我们预计,我们的研究结果将提供有关 睡眠和/或昼夜节律紊乱的时间顺序以及蛋白质的积累和扩散 聚集体如AD中的p-t和Aβ。除此之外,这项研究的结果将为以下疾病的合理治疗提供信息: 治疗AD的睡眠障碍。

项目成果

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Lea Tenenholz Grinberg其他文献

Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis
  • DOI:
    10.1016/j.neurobiolaging.2024.11.001
  • 发表时间:
    2025-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marcelo Kenzo Naya Takahashi;Regina Silva Paradela;Lea Tenenholz Grinberg;Renata Elaine Paraizo Leite;Daniela Souza Farias-Itao;Vitor Ribeiro Paes;Maria Eduarda Braga;Michel Satya Naslavsky;Mayana Zatz;Wilson Jacob-Filho;Ricardo Nitrini;Carlos Augusto Pasqualucci;Claudia Kimie Suemoto
  • 通讯作者:
    Claudia Kimie Suemoto
Cause of Death Determined by Full-body Autopsy in Neuropathologically Diagnosed Dementias
通过全身尸检确定神经病理学诊断的痴呆症的死因
  • DOI:
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    Beatriz Astolfi Neves;Paula Villela Nunes;Roberta Diehl Rodriguez;Atmis Medeiros Haidar;Renata Elaine Paraizo Leite;C. Nascimento;Carlos Augusto Pasqualucci;R. Nitrini;W. Jacob;B. Lafer;Lea Tenenholz Grinberg;Claudia Kimie Suemoto
  • 通讯作者:
    Claudia Kimie Suemoto

Lea Tenenholz Grinberg的其他文献

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{{ truncateString('Lea Tenenholz Grinberg', 18)}}的其他基金

Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression
使用 MRI 对脑铁和蛋白质聚集进行成像,以评估阿尔茨海默病的病理学和进展
  • 批准号:
    10563181
  • 财政年份:
    2021
  • 资助金额:
    $ 1.38万
  • 项目类别:
Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression
使用 MRI 对脑铁和蛋白质聚集进行成像,以评估阿尔茨海默病的病理学和进展
  • 批准号:
    10331335
  • 财政年份:
    2021
  • 资助金额:
    $ 1.38万
  • 项目类别:
Core C: Human Tissue Validation
核心 C:人体组织验证
  • 批准号:
    10295515
  • 财政年份:
    2021
  • 资助金额:
    $ 1.38万
  • 项目类别:
Better memory with literacy acquisition later in life: a randomized controlled trial
晚年读写能力提高记忆力:一项随机对照试验
  • 批准号:
    10054007
  • 财政年份:
    2020
  • 资助金额:
    $ 1.38万
  • 项目类别:
Better memory with literacy acquisition later in life: a randomized controlled trial
晚年读写能力提高记忆力:一项随机对照试验
  • 批准号:
    10263225
  • 财政年份:
    2020
  • 资助金额:
    $ 1.38万
  • 项目类别:
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP
阿尔茨海默病和 PSP 睡眠觉醒行为的临床特征和神经病理学基础
  • 批准号:
    10112791
  • 财政年份:
    2019
  • 资助金额:
    $ 1.38万
  • 项目类别:
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:
    10636812
  • 财政年份:
    2019
  • 资助金额:
    $ 1.38万
  • 项目类别:
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:
    10441484
  • 财政年份:
    2019
  • 资助金额:
    $ 1.38万
  • 项目类别:
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:
    9803439
  • 财政年份:
    2019
  • 资助金额:
    $ 1.38万
  • 项目类别:
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP
阿尔茨海默病和 PSP 睡眠觉醒行为的临床特征和神经病理学基础
  • 批准号:
    10589765
  • 财政年份:
    2019
  • 资助金额:
    $ 1.38万
  • 项目类别:

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