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 突变导致常染色体显性遗传性脑动脉病，伴有皮质下梗塞和白细胞介素科脑病 (CADASIL)，一种以小血管疾病和白斑为特征的神经系统疾病早老蛋白 1 (PSEN1) 的突变是早发性家族性阿尔茨海默病的最常见原因。尽管 CADASIL 和 PSEN1 相关 AD 被认为是纯粹的疾病模型，有证据表明潜在的机制重叠，因为 PSEN1 功能是激活包括 Notch3 在内的 Notch 受体支持这一观点，临床研究显示大量的白质分布。 PSEN1 突变携带者的缓解和 CADASIL 患者的脑脊液分析显示出变化我们发现了 SVD 及其相关的白质疾病。由于保护血管和白细胞的稳态 PSEN1/NOTCH3 通路失调而发生成年人在生理条件下的物质完整性和在家庭形式的去功能障碍中为了检验这一假设，我们建议利用带有 Notch3 和 Psen1 突变的动物模型。我们还将对 PSEN1 和 NOTCH3 突变携带者的死后人体组织进行平行研究我们提出两个研究目标：目标 1：检查 PSEN1/NOTCH3 信号传导与血管变性之间的功能联系我们将使用 Notch3 和 Psen1 突变小鼠模型。以及来自 CADASIL 和 AD 患者的死后人体组织，以检查 PSEN1/NOTCH3 的作用我们将在携带单一突变的小鼠和携带 CADASIL 的小鼠中进行研究。 Notch3 突变和导致 AD 的 PSEN1 突变。目标 2：研究 PSEN1/NOTCH3 信号传导与脑白质分布之间的功能联系我们将使用 Notch3 和 PSEN1 突变小鼠模型和死后人体组织来检查。 PSEN1/NOTCH3 通路对白质变性的作用我们将在小鼠表达中进行分析。在壁细胞以及在少突胶质细胞中表达突变型 Notch3 的小鼠中进行 CADASIL 突变，这是另一种研究 Notch3 表达位点与 CADASIL 病理学有关。这些实验将告诉我们 PSEN1/NOTCH3 功能障碍对分子信号传导的影响程度与 SVD 和白质变性有关的途径可能导致识别新的治疗方法。