Preclinical investigation of common mechanistic links between aberrant protein aggregation and blood-brain barrier dysfunction in Alzheimer's disease and Alzheimer's related dementias (AD/ADRD)

阿尔茨海默病和阿尔茨海默病相关痴呆 (AD/ADRD) 中异常蛋白聚集与血脑屏障功能障碍之间常见机制联系的临床前研究

基本信息

  • 批准号:
    10037968
  • 负责人:
  • 金额:
    $ 263.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-30 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY The blood-brain barrier (BBB) has a fundamental role in maintaining brain tissue homeostasis. While dysfunction of the BBB is a common feature of many neurodegenerative diseases, including Alzheimer’s disease (AD) and AD-related dementias (ADRD), but also small vessel diseases (SVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it is still unclear whether BBB dysfunction precedes the onset of neurological disorders or is a consequence of their aggravating pathology. Converging evidence indicates that dysfunction of the BBB correlates with an abnormal perivascular deposition and aggregation of proteins such as amyloid-β (Aβ) and tau in AD, or granular osmiophilic material (GOM) and the NOTCH3 ectodomain in CADASIL. These proteins are known to interact with the proteins that make up the extracellular matrix (ECM) and the basement membranes of cerebral blood vessels. Cumulative protein aggregation leads to functional impairment of the ECM and causes damage to the cellular components of the neurovascular unit (NVU), promoting BBB breakdown and affecting the mechanisms of protein transport across the BBB. Thus, there is a vicious cycle between BBB dysfunction and aberrant protein accumulation that progresses with age, leading to cognitive impairment and death. Understanding this cycle is crucial to elucidate the mechanistic links between BBB dysfunction and dementia, and to identify therapeutic opportunities to preserve BBB function. We hypothesize that aberrant protein accumulation and BBB dysfunction contribute synergistically in AD/ADRD and CADASIL through a common mechanistic link. Using well-established mouse models of AD and CADASIL, we propose to investigate the effects of perivascular protein aggregation on both structural (Aim 1) and functional (Aim 2) properties of the BBB, to understand how perivascular protein aggregation relates to structural changes of the NVU that leads to BBB dysfunction. We will then investigate whether the mechanical disruption of the BBB contributes to perivascular protein deposition and aggregation (Aim 3). These experiments will provide crucial knowledge on the molecular and cellular mechanisms of interaction between protein aggregation and BBB breakdown, and may ultimately unravel novel therapeutic targets aimed at preserving cerebrovascular health and BBB function.
PROJECT SUMMARY The blood-brain barrier (BBB) has a fundamental role in maintaining brain tissue homeostasis. While dysfunction of the BBB is a common feature of many neurodegenerative diseases, including Alzheimer’s disease (AD) and AD-related dementias (ADRD), but also small vessel diseases (SVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it is still unclear whether BBB dysfunction precedes the onset of neurological disorders or is a consequence of their aggravating pathology. Converging evidence indicates that dysfunction of the BBB correlates with an abnormal perivascular deposition and aggregation of proteins such as amyloid-β (Aβ) and tau in AD, or granular osmiophilic material (GOM) and the NOTCH3 ectodomain in CADASIL. These proteins are known to interact with the proteins that make up the extracellular matrix (ECM) and the basement membranes of cerebral blood vessels. Cumulative protein aggregation leads to functional impairment of the ECM and causes damage to the cellular components of the neurovascular unit (NVU), promoting BBB breakdown and affecting the mechanisms of protein transport across the BBB. Thus, there is a vicious cycle between BBB dysfunction and aberrant protein accumulation that progresses with age, leading to cognitive impairment and death. Understanding this cycle is crucial to elucidate the mechanistic links between BBB dysfunction and dementia, and to identify therapeutic opportunities to preserve BBB function. We hypothesize that aberrant protein accumulation and BBB dysfunction contribute synergistically in AD/ADRD and CADASIL through a common mechanistic link. Using well-established mouse models of AD and CADASIL, we propose to investigate the effects of perivascular protein aggregation on both structural (Aim 1) and functional (Aim 2) properties of the BBB, to understand how perivascular protein aggregation relates to structural changes of the NVU that leads to BBB dysfunction. We will then investigate whether the mechanical disruption of the BBB contributes to perivascular protein deposition and aggregation (Aim 3). These experiments will provide crucial knowledge on the molecular and cellular mechanisms of interaction between protein aggregation and BBB breakdown, and may ultimately unravel novel therapeutic targets aimed at preserving cerebrovascular health and BBB function.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Afonso C Silva其他文献

脳主幹動脈瘤狭窄閉塞症例に対し脳血流SPECTで脳血管反応性を評価するために用いられるacetazolamide静脈内投与の副作用
静脉注射乙酰唑胺用于通过脑血流SPECT评估脑血管反应性在主脑动脉动脉瘤狭窄和闭塞的情况下的副作用
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    河合裕子;青木伊知男;梅田雅宏;樋口敏宏;樋口真人;Afonso C Silva;田中忠蔵;斎藤秀夫
  • 通讯作者:
    斎藤秀夫
Manganese-enhanced MRIを用いた虚血脳における組織変化の検出
使用锰增强 MRI 检测缺血脑中的组织变化
  • DOI:
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    0
  • 作者:
    河合裕子;青木伊知男;梅田雅宏;樋口敏宏;樋口真人;Afonso C Silva;田中忠蔵
  • 通讯作者:
    田中忠蔵

Afonso C Silva的其他文献

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{{ truncateString('Afonso C Silva', 18)}}的其他基金

Multimodal Disease Characterization Core
多模式疾病表征核心
  • 批准号:
    10494773
  • 财政年份:
    2022
  • 资助金额:
    $ 263.05万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10494770
  • 财政年份:
    2022
  • 资助金额:
    $ 263.05万
  • 项目类别:
Project 3: Multi-modal phenotypic Characterization of marmoset models of Late Onset Alzheimer's Disease
项目3:晚发性阿尔茨海默病狨猴模型的多模式表型表征
  • 批准号:
    10494777
  • 财政年份:
    2022
  • 资助金额:
    $ 263.05万
  • 项目类别:
Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding
基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证
  • 批准号:
    10668407
  • 财政年份:
    2021
  • 资助金额:
    $ 263.05万
  • 项目类别:
Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding
基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证
  • 批准号:
    10468141
  • 财政年份:
    2021
  • 资助金额:
    $ 263.05万
  • 项目类别:
Development and Validation of a Marmoset Model of Late-Onset Alzheimer Disease Based on Tau Seeding
基于 Tau 接种的晚发性阿尔茨海默病狨猴模型的开发和验证
  • 批准号:
    10281602
  • 财政年份:
    2021
  • 资助金额:
    $ 263.05万
  • 项目类别:

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