Charting vascular contributions to white matter disease in familial Alzheimer's disease and CADASIL

绘制血管对家族性阿尔茨海默病和 CADASIL 中白质疾病的影响

基本信息

批准号：
10004339
负责人：
Joseph Arboleda-Velasquez
金额：
$ 4.99万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004339
关键词：
Academic Medical Centers Adult Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Animal Model Autopsy Biochemical Biological Biological Assay Blood Blood Vessels Boston Brain CADASIL Cell Fractionation Cell Survival Cells Cerebral Amyloid Angiopathy Cerebrospinal Fluid Clinical Clinical Research Colombia Corpus Callosum Critical Pathways Dementia Disease model Early Onset Familial Alzheimer&apos s Disease Electron Microscopy Family Functional disorder General Hospitals Generations Histopathology Homeostasis Human Immunohistochemistry Link Metabolism Microvascular Dysfunction Modeling Molecular Mus Mutation NOTCH3 gene Neuroglia Neurologic Occipital lobe Oligodendroglia Pathologic Pathway interactions Patients Physiological Research Research Personnel Role Senile Plaques Signal Transduction Site Stains Structure Temporal Lobe Testing Tissues Universities Vascular Dementia Vascular Permeabilities White Matter Disease Work brain parenchyma experimental study familial Alzheimer disease frontal lobe human tissue in vivo Model laser capture microdissection mouse model mutant mutant mouse model mutation carrier notch protein novel therapeutic intervention presenilin presenilin-1 preservation tau Proteins transcriptome sequencing transcriptomics vascular contributions white matter

项目摘要

Mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leu- koencephalopathy (CADASIL), a neurological condition characterized by small vessel disease and white mat- ter degeneration. Mutations in Presenilin 1 (PSEN1) are the most prevalent cause of early onset familial Alz- heimer’s disease (AD). Though CADASIL and PSEN1-associated AD are considered pure disease models, there is evidence of potential mechanistic overlap because PSEN1 function is required for the activation of Notch receptors including Notch3. Supporting this view, clinical studies showed substantial white matter dis- ease in PSEN1 mutation carriers and cerebral spinal fluid analyses of CADASIL patients show changes indica- tive of abnormal amyloid metabolism. We hypothesize that SVD and its associated white matter disease occurs due to dysregulation of homeostatic PSEN1/NOTCH3 pathways that preserve vessel and white matter integrity in adults under physiological conditions and are dysfunctional in familial forms of de- mentia. To test this hypothesis, we propose to leverage our animal models with Notch3 and Psen1 mutations. We will also conduct parallel studies in postmortem human tissue from PSEN1 and NOTCH3 mutation carriers to identify common pathobiological mechanisms. We propose two research aims: Aim 1: To examine functional links between PSEN1/NOTCH3 signaling and vascular degeneration us- ing mouse models and postmortem human tissue. We will use Notch3 and Psen1 mutant mouse models and postmortem human tissue from CADASIL and AD patients to examine the role of the PSEN1/NOTCH3 pathway on SVD. We will conduct studies in mice carrying single mutations and in mice carrying a CADASIL mutation in Notch3 and an AD-causing PSEN1 mutation. Aim 2: To investigate functional links between PSEN1/NOTCH3 signaling and brain white matter dis- ease. We will use Notch3 and PSEN1 mutant mouse models and postmortem human tissue to examine the role of the PSEN1/NOTCH3 pathway on white matter degeneration. We will conduct analyses in mice express- ing CADASIL mutations in mural cells and also in mice expressing mutant Notch3 in oligodendrocytes, another site of Notch3 expression that has been implicated in CADASIL pathobiology. These experiments will tell us the extent to which PSEN1/NOTCH3 dysfunction impact signaling in molecular pathways implicated in SVD and white matter degeneration potentially leading to the identification of novel therapeutic approaches.

NOTCH3突变引起脑常染色体显性动脉炎，具有下皮质下的小动脉和leu- Koencephalopathy（Cadasil），一种以小血管疾病和白色垫子为特征的神经系统疾病变性。老年蛋白1（PSEN1）中的突变是早期发作家族性alz-的最普遍原因海默氏病（AD）。尽管Cadasil和PSEN1相关的AD被认为是纯疾病模型，但有潜在机械重叠的证据，因为激活需要PSEN1功能包括Notch3在内的Notch受体。支持这一观点，临床研究表明，大量的白质疾病 CADASIL患者的PSEN1突变载体和脑脊髓液分析的易于症状显示出变化异常淀粉样代谢。我们假设SVD及其相关的白质疾病由于稳态和白色的稳态PSEN1/NOTCH3途径的失调而发生在生理条件下成人的物质完整性，在家庭形式的家庭形式中功能失调精神病。为了检验这一假设，我们建议用Notch3和Psen1突变利用动物模型。我们还将在PSEN1和NOTCH3突变载体中对死后人体组织进行平行研究确定常见的病理学机制。我们提出了两个研究目的：目标1：检查PSEN1/NOTCH3信号传导与血管变性之间的功能联系小鼠模型和死后人体组织。我们将使用Notch3和PSEN1突变鼠标模型来自卡达西尔和AD患者的死后人体组织检查PSEN1/NOTCH3的作用 SVD的途径。我们将在携带单个突变和携带Cadasil的小鼠的小鼠中进行研究 Notch3中的突变和引起AD的PSEN1突变。目标2：研究PSEN1/NOTCH3信号传导与脑白质之间的功能联系舒适。我们将使用Notch3和PSEN1突变小鼠模型以及验尸后人体组织检查 PSEN1/NOTCH3途径在白质变性中的作用。我们将对小鼠进行分析 - 在壁细胞中的Cadasil突变以及在少突胶质细胞中表达突变体Notch3的小鼠中，另一种在Cadasil病理生物学中已隐含的Notch3表达部位。这些实验将告诉我们PSEN1/NOTCH3功能障碍在分子中影响信号的程度 SVD和白质变性实施的途径可能导致新颖的识别治疗方法。