Central noradrenergic mechanisms of cerebrovascular pathology in Alzheimer's disease

阿尔茨海默病脑血管病理学的中枢去甲肾上腺素能机制

• 批准号: 10343722
• 负责人: Scott E Counts
• 金额: $ 46.8万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343722
• 关键词: Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid; Attention; Automobile Driving; Autopsy; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain region; Calcium Signaling; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrovascular Physiology; Chemicals; Clinical; Cognitive; Data; Deafferentation procedure; Disease; Dopamine-beta-monooxygenase; Extravasation; Fiber; Genes; Harvest; Human; Immunoglobulin G; Immunotoxins; Impaired cognition; Impairment; In Vitro; Lasers; Lesion; Link; Magnetic Resonance Imaging; Measures; Mediating; Memory; Memory impairment; Modeling; Modification; Molecular; Myography; Nerve Degeneration; Neurons; Neurotoxins; Norepinephrine; Outcome; Oxidative Stress; Oxygen Consumption; Pathogenicity; Pathology; Pathway interactions; Performance; Perfusion; Permeability; Physiology; Play; Prefrontal Cortex; Prodrugs; Prosencephalon; RNA analysis; Rattus; Regimen; Respiration; Role; Senile Plaques; Signal Pathway; Signal Transduction; Solid; Stroke; Study Subject; System; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Vascular Cognitive Impairment; Vascular Diseases; Vascular Permeabilities; Vascular remodeling; amnestic mild cognitive impairment; arteriole; atomoxetine; blood-brain barrier permeabilization; brain endothelial cell; cerebrovascular; cerebrovascular pathology; cognitive function; design; executive function; human tissue; hypertensive; in vivo; inhibitor; insight; interest; locus ceruleus structure; neuroinflammation; neuron loss; neuropathology; neurovascular coupling; noradrenergic; novel; novel therapeutics; nuclear respiratory factor; parenchymal arterioles; pathomechanics; pre-clinical; pressure; prodromal Alzheimer' s disease; receptor; religious order study; reuptake; tau Proteins; transcriptome sequencing; treatment group; vascular contributions; vascular risk factor; virtual

Project Summary The main hypothesis of this proposal is that degeneration of the locus coeruleus (LC) noradrenergic projection system promotes cognitive impairment in Alzheimer’s disease (AD) by driving forebrain cerebrovascular dysfunction. We recently demonstrated that LC neuron loss occurs in amnestic mild cognitive impairment (aMCI) and correlates with poorer cognitive function. Hence, understanding how LC degeneration impairs cognition may open up new therapeutic avenues. To date, most studies have focused on the role of the LC in regulating AD neuropathology, yet virtually no attention has been paid to the role of the LC in regulating cerebrovascular permeability and perfusion in AD. To gauge the scientific premise for pursuing this question, we administered a dopamine-β-hydroxylase IgG-saporin (DBH-SAP) immunotoxin into the prefrontal cortex (PFC) of Tg344-19 AD rats, which mimicked LC neuron and fiber loss and resulted in memory impairments. Strikingly, postmortem analysis revealed evidence of widespread blood-brain barrier leakage and increased cerebral amyloid angiopathy in DBH-SAP-lesioned AD rats compared to control IgG-saporin (CTL-SAP) rats. Moreover, pressure myography studies showed blunted vasoreactivity of PFC parenchymal arterioles following DBH-SAP lesions. To begin to understand the mechanisms for these LC-mediated pathologies, RNA sequencing was performed on laser-captured PFC vessels from Rush Religious Orders Study (RROS) subjects. These data revealed a dysregulation of genes mediating vessel permeability and calcium signaling in aMCI and AD compared to controls. Many of these genes were also dysregulated in vessels harvested from DBH-SAP-lesioned AD rats, suggesting specific pathomechanic pathways linking LC degeneration with forebrain vascular dysfunction. Therefore, we designed our Specific Aims to test the extent to which LC degeneration drives cerebrovascular pathology in target fields (Aim 1) and the potential mechanisms underlying this phenomenon (Aim 2). In Aim 1, Tg344-19 AD rats will be administered DBH-SAP or CTL-SAP in the PFC in the presence or absence of the norepinephrine pro-drug L-DOPS or the reuptake inhibitor atomoxetine. Rats will be assessed for memory function and for cortical perfusion by MRI. Pressure myography studies will analyze vessel physiology and postmortem analysis will quantify vascular and AD-like pathology. Spontaneously Hypertensive Stroke Prone rats will also be included to test whether LC cell loss exacerbates vascular risk factors. In Aim 2, PFC parenchymal vessels from RROS subjects will be analyzed by RNA-Seq. Target genes that are also dysregulated in PFC vessels from DBH-SAP rats will be validated and tested for their role in vascular dysfunction using in vitro mechanistic assays. If successful, this proposal will show that 1) LC degeneration is a nexus lesion that impacts both vascular and neuropathology during the earliest stages of AD, and that 2) targeting noradrenergic mechanistic pathways in small vessels may allow for more comprehensive disease modification in AD by reducing vascular contributions to cognitive impairment.

项目概要 该提案的主要假设是蓝斑（LC）去甲肾上腺素能投射的退化 系统通过驱动前脑脑血管促进阿尔茨海默病（AD）的认知障碍 功能障碍。我们最近证明，遗忘性轻度认知障碍会发生 LC 神经元丢失 (aMCI) 并与较差的认知功能相关。因此，了解 LC 变性如何损害 认知可能开辟新的治疗途径。迄今为止，大多数研究都集中在 LC 在 调节 AD 神经病理学，但实际上没有注意到 LC 在调节中的作用 AD 中的脑血管通透性和灌注。为了衡量解决这个问题的科学前提， 我们将多巴胺-β-羟化酶 IgG-皂素 (DBH-SAP) 免疫毒素注射到前额皮质 Tg344-19 AD 大鼠的 PFC（PFC），模仿 LC 神经元和纤维损失并导致记忆障碍。 引人注目的是，尸检分析揭示了广泛的血脑屏障渗漏和增加的证据。 与对照 IgG-皂素 (CTL-SAP) 大鼠相比，DBH-SAP 损伤的 AD 大鼠脑淀粉样血管病。 此外，压力肌动描记研究显示 PFC 实质小动脉的血管反应性减弱 DBH-SAP 病变。为了开始了解这些 LC 介导的病理机制，RNA 对来自 Rush Religious Orders Study (RROS) 的激光捕获的 PFC 血管进行测序 科目。这些数据揭示了介导血管通透性和钙信号传导的基因失调 aMCI 和 AD 与对照相比。许多这些基因在从以下来源收获的血管中也失调 DBH-SAP 损伤的 AD 大鼠，表明 LC 变性与 前脑血管功能障碍。因此，我们设计了具体目标来测试 LC 的程度 退化驱动目标区域的脑血管病理（目标 1）及其潜在机制 这一现象的背后（目标 2）。在目标 1 中，Tg344-19 AD 大鼠将接受 DBH-SAP 或 CTL-SAP 在存在或不存在去甲肾上腺素前药 L-DOPS 或再摄取抑制剂的情况下，在 PFC 中 阿托莫西汀。将通过 MRI 评估大鼠的记忆功能和皮质灌注。压力 肌电图研究将分析血管生理学，尸检分析将量化血管和 AD 样疾病 病理。自发性高血压中风倾向大鼠也将被纳入测试是否 LC 细胞丢失 加剧血管危险因素。在目标 2 中，来自 RROS 受试者的 PFC 实质血管将通过以下方式进行分析： RNA测序。 DBH-SAP 大鼠 PFC 血管中也失调的靶基因将得到验证并 使用体外机制测定测试了它们在血管功能障碍中的作用。如果成功，该提案将 表明 1) LC 变性是一种连接病变，在治疗过程中会影响血管和神经病理学 AD 的最早阶段，并且 2) 针对小血管中的去甲肾上腺素能机制途径可能允许 通过减少血管对认知障碍的影响，对 AD 进行更全面的疾病治疗。