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

• 批准号: 10037968
• 负责人: Afonso C Silva
• 金额: $ 263.05万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10037968
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein; Basement membrane; Behavioral; Behavioral Assay; Biochemical; Blood - brain barrier anatomy; Blood Preservation; Blood Vessels; Brain; CADASIL; Carrier Proteins; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular system; Cessation of life; Chronic; Data; Dementia; Deposition; Endothelial Cells; Extracellular Matrix; Functional disorder; Goals; Histologic; Homeostasis; Image; Impaired cognition; Investigation; Knowledge; Lead; Link; Lymphatic System; Measures; Mechanics; Microbubbles; Microvascular Dysfunction; Molecular; NOTCH3 gene; Neurodegenerative Disorders; Pathologic; Pathology; Peptide Hydrolases; Pericytes; Plasma; Property; Proteins; Role; Smooth Muscle Myocytes; Structure; Techniques; Testing; Therapeutic; Ultrasonography; Vascular Smooth Muscle; Vascular System; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; brain tissue; cerebrovascular; cerebrovascular health; experimental study; functional disability; functional status; mouse model; nervous system disorder; neurovascular unit; new therapeutic target; pre-clinical; preservation; protein aggregation; protein transport; receptor; tau Proteins

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.

项目摘要 血脑屏障（BBB）在维持脑组织稳态方面具有基本作用。尽管 BBB功能障碍是许多神经退行性疾病的常见特征，包括阿尔茨海默氏病 （AD）和与广告相关的痴呆症（ADRD），但也是小血管疾病（SVD），例如大脑常染色体 具有下皮质下的动脉病毒和白细胞病（卡达西尔），仍然尚不清楚是否仍然不清楚 BBB功能障碍先于神经系统疾病的发作，或者是其加重病理学的结果。 融合证据表明，BBB的功能障碍与血管周期异常相关 蛋白质（例如AD中的淀粉样蛋白（Aβ）和Tau）的蛋白质的聚集，或颗粒状渗透材料（GOM）和 CADASIL中的Notch3外生域。已知这些蛋白质与组成的蛋白质相互作用 细胞外基质（ECM）和脑血管的基底膜。累积蛋白 聚集会导致ECM的功能障碍，并对细胞成分造成损害 神经血管单元（NVU），促进BBB分解并影响越过蛋白质的机制 BBB。那就是BBB功能障碍与异常蛋白积累之间存在恶性循环， 随着年龄的增长，导致认知障碍和死亡。了解这一周期对于阐明 BBB功能障碍与痴呆症之间的机械联系，并确定治疗机会 保留BBB功能。我们假设异常蛋白的积累和BBB功能障碍有助于 通过共同的机械链接在AD/ADRD和CADASIL中协同作用。使用良好的鼠标 AD和CADASIL的模型，我们提议研究周围蛋白聚集对这两者的影响 BBB的结构（AIM 1）和功能性（AIM 2）特性，以了解周围蛋白如何 聚集与导致BBB功能障碍的NVU的结构变化有关。然后我们将调查 BBB的机械破坏是否有助于周围蛋白质沉积和聚集 （目标3）。这些实验将提供有关分子和细胞机制的关键知识 蛋白质聚集与BBB分解之间的相互作用，并最终可以解散新的疗法 旨在保留脑血管健康和BBB功能的目标。