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

NOTCH3基因突变导致常染色体显性遗传性脑动脉病伴皮质下梗塞和白血球样变性 脑白质病变(CADASIL)是一种以小血管病变和白色垫子为特征的神经系统疾病。 而不是退化。早老素1(PSEN1)基因突变是早发性家族性阿尔茨海默病最常见的原因。 海默病(AD)。尽管CADASIL和PSEN1相关的AD被认为是纯粹的疾病模型， 有证据表明可能存在机械重叠，因为激活PSEN1功能是必需的 Notch3等Notch3受体。支持这一观点的临床研究显示，大量脑白质病变。 CADASIL患者PSEN1突变携带者和脑脊液分析显示EASE指标发生变化 与淀粉样蛋白代谢异常有关。我们假设SVD及其相关的脑白质疾病 发生是由于保护血管和白质的稳态PSEN1/NOTCH3通路失调所致 生理条件下成人的物质完整性和家族性痴呆的功能障碍 提过了。为了验证这一假设，我们建议利用我们的Notch3和PSEN1突变的动物模型。 我们还将在PSEN1和NOTCH3突变携带者的死后人类组织中进行平行研究 以确定常见的病理生物学机制。我们提出了两个研究目标： 目的1：研究PSEN1/NOTCH3信号与血管退行性变之间的功能联系。 ING小鼠模型和死后人体组织。我们将使用Notch3和PSEN1突变小鼠模型 并从CADASIL和AD患者的身体组织中检测PSEN1/NOTCH3的作用 SVD的通路。我们将在携带单一突变的小鼠和携带CADASIL的小鼠身上进行研究 Notch3突变和导致AD的PSEN1突变。 目的2：研究PSEN1/NOTCH3信号与脑白质病变的功能联系。 放松点。我们将使用Notch3和PSEN1突变小鼠模型和死后人类组织来检查 PSEN1/NOTCH3通路在白质变性中的作用我们将在MICE EXPRESS中进行分析- 壁细胞中的ING CADASIL突变以及在少突胶质细胞中表达突变Notch3的小鼠，另一种 与CADASIL病理生物学有关的Notch3表达部位。 这些实验将告诉我们PSEN1/NOTCH3功能障碍对分子中信号的影响程度 与SVD和白质变性有关的通路可能导致对小说的识别 治疗方法。

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.