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: 9765740
• 负责人: Scott E Counts
• 金额: $ 49.05万
• 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/9765740
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; 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; Gap Junctions; 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; Religion and Spirituality; 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; brain endothelial cell; cerebrovascular; cerebrovascular pathology; cognitive function; design; executive function; human tissue; in vivo; inhibitor/antagonist; insight; interest; locus ceruleus structure; neuroinflammation; neuron loss; neuropathology; neurovascular coupling; noradrenergic; novel; novel therapeutics; nuclear respiratory factor; parenchymal arterioles; pathomechanics; pre-clinical; pressure; receptor; 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.

项目摘要 这一建议的主要假设是蓝斑（LC）去甲肾上腺素能投射的变性， 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，LC神经元的损失发生在遗忘的轻度认知障碍 （aMCI），并与较差的认知功能相关。因此，了解LC变性如何损害 认知可能会开辟新的治疗途径。到目前为止，大多数研究都集中在LC的作用， 调节AD神经病理学，但几乎没有注意到LC在调节AD神经病理学中的作用。 脑血管通透性和灌注。为了衡量这个问题的科学前提， 我们将多巴胺-β-羟化酶IgG-皂草素（DBH-SAP）免疫毒素注入前额叶皮层， (PFC)的Tg 344 -19 AD大鼠，其模拟LC神经元和纤维损失并导致记忆障碍。 引人注目的是，死后分析显示了广泛的血脑屏障渗漏的证据， DBH-SAP损伤AD大鼠与对照IgG-皂草素（CTL-SAP）大鼠相比的脑淀粉样血管病。 此外，压力肌描记术研究显示， DBH-SAP病变。为了开始了解这些LC介导的病理机制，RNA 对来自拉什宗教教团研究（Rush Religious Orders Study，RROS）的激光捕获PFC血管进行测序 科目这些数据揭示了在糖尿病患者中，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。这些基因中的许多也在从血管中获得的血管中失调。 DBH-SAP损伤的AD大鼠，表明连接LC变性与AD的特定病理机制通路。 前脑血管功能障碍因此，我们设计了我们的具体目标，以测试在多大程度上LC 退变驱动靶区脑血管病变（目标1）和潜在机制 这一现象的根源（目标2）。在目的1中，Tg 344 -19 AD大鼠将被施用DBH-SAP或CTL-SAP 在PFC中，存在或不存在去甲肾上腺素前体药物L-DOPS或再摄取抑制剂 托莫西汀。将通过MRI评估大鼠的记忆功能和皮质灌注。压力 肌造影研究将分析血管生理学，死后分析将量化血管和AD样 病理还将包括自发性高血压中风倾向大鼠以测试LC细胞损失是否 加重血管风险因素。在目标2中，将通过以下方法分析来自RROS受试者的PFC实质血管： RNA测序将验证在DBH-SAP大鼠PFC血管中也失调的靶基因， 使用体外机制分析测试它们在血管功能障碍中的作用。如果成功的话，这一提议将 显示1）LC变性是一种关系性病变，在治疗期间影响血管和神经病理学。 AD的早期阶段，以及2）靶向小血管中的去甲肾上腺素能机制通路可能允许 通过减少血管对认知障碍的贡献，更全面地改善AD的疾病。