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: 9897460
• 负责人: Scott E Counts
• 金额: $ 51万
• 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/9897460
• 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; 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; 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; 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; 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 系统通过驱动前脑血管促进阿尔茨海默病(AD)患者的认知损害 功能障碍。我们最近证实，遗忘性轻度认知障碍会导致LC神经元丢失 (AMCI)，并与较差的认知功能相关。因此，了解LC退变是如何损害的 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在 调节AD的神经病理，但几乎没有注意到LC在调节中的作用 阿尔茨海默病患者的脑血管通透性和血流灌注率。为了衡量追问这个问题的科学前提， 我们将多巴胺-β-羟基酶免疫毒素(DBH-SAP)注射到前额叶皮质 Tg344-19 AD大鼠(PFC)，模拟LC神经元和纤维丢失，导致记忆障碍。 令人惊讶的是，尸检分析显示，有证据表明血脑屏障广泛渗漏和增加 DBH-SAP损毁AD大鼠与对照组(CTL-SAP)大鼠脑淀粉样血管病变的比较。 此外，压力肌肉造影术研究显示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 对来自拉什宗教教团研究(RROS)的激光捕获的PFC血管进行测序 研究对象。这些数据揭示了介导血管通透性和钙信号的基因的失调。 AMCI和AD与对照组比较。这些基因中的许多也在从 DBH-SAP损毁AD大鼠，提示特定的病理机制将LC变性与 前脑血管功能障碍。因此，我们设计了具体的目标来测试LC在多大程度上 退行性病变导致靶区脑血管病变(目标1)及其可能机制 这一现象的根本原因(目标2)。在AIM 1中，Tg344-19 AD大鼠将被给予DBH-SAP或CTL-SAP 在存在或不存在去甲肾上腺素前体药物L-DOPS或重摄取抑制剂的情况下进行PFC 阿莫西汀。将通过核磁共振对大鼠的记忆功能和皮质灌注量进行评估。压力 肌肉造影术研究将分析血管生理学，尸检分析将量化血管和AD样 病理学。自发性高血压卒中倾向大鼠也将被包括在内，以测试LC细胞是否丢失 加重血管风险因素。在目标2中，来自RROS受试者的PFC实质血管将通过 RNA-Seq.在DBH-SAP大鼠的PFC血管中也存在调控异常的靶基因将被验证并 使用体外机械分析测试它们在血管功能障碍中的作用。如果成功，这项提议将 结果表明：1)LC变性是一种影响血管和神经病理的神经中枢病变。 阿尔茨海默病的早期阶段，2)以小血管中的去甲肾上腺素能机械通路为靶点可能允许 通过减少血管对认知损害的贡献，更全面地改善AD的疾病。