Metabolic and Vascular Factors in tau pathogenesis

tau 发病机制中的代谢和血管因素

基本信息

批准号：
10414102
负责人：
SALLY ANN FRAUTSCHY
金额：
$ 68.34万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414102
关键词：
3xTg-AD mouse APP-PS1 Acceleration Address Adverse effects Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Angiotensin II Receptor Antihypertensive Agents Apolipoprotein E Attenuated Behavior Behavioral Biochemical Biological Markers Blood Plasma Volume Blood Pressure Blood Vessels Brain Breeding Cerebrospinal Fluid Cerebrovascular Disorders Cilostazol Clinic Cognitive Combined Modality Therapy Complex Consensus Data Dementia Demyelinations Drops Endothelial Cells Endothelium Estrogen Antagonists Estrogen Receptors Estrogens Exhibits Experimental Designs Extravasation FDA approved Female Genetic Glial Fibrillary Acidic Protein Goals Human Hypertension Inbred WKY Rats Individual Inflammation Intervention Knowledge Longitudinal Studies Losartan Menopause Metabolic Methods Microglia Microvascular Dysfunction Mitochondria Modeling Mus Nerve Degeneration Neuroglia Neuropil Neuropsychology Oral Pathogenesis Pathologic Pathology Pathway interactions Pericytes Persons Pharmaceutical Preparations Phenotype Plasma Polypharmacy Population Postmenopause Pre-Clinical Model Publishing RNA Rat Strains Rattus Research Priority Risk Risk Factors Rodent Severities Signal Transduction Stroke Study models Surrogate Markers Tauopathies Testing Therapeutic Transgenes Validation Vascular Cognitive Impairment Vascular Diseases Vascular Endothelial Growth Factors Woman antagonist apolipoprotein E-3 apolipoprotein E-4 base behavioral phenotyping blood pressure control cell type cerebrovascular cohort comorbidity dementia risk diagnostic criteria drug efficacy epidemiology study exosome experience high salt diet human female hypertensive improved inhibitor male men mixed dementia mutant neuroimaging neuroinflammation neuropsychiatry neurovascular injury neurovascular unit normotensive novel protective effect screening sex spatial memory synergism tau Proteins tool transcriptome sequencing vascular factor vascular inflammation β-amyloid burden

项目摘要

ABSTRACT This revised proposal utilizes our recently described novel model of Mixed Dementia (MxD) (Denver et al. 2019), the most prevalent dementia, yet MxD subjects are often excluded from AD trials. There is a paucity of models with coexisting vascular and Alzheimer's (AD) pathologies, in addition to a lack of consensus in neuropathological (or neuropsychiatric) diagnostic criteria for MxD. Therefore, this proposal seeks to identify synergistic and independent interactions between AD and hypertension-associated cerebrovascular disease factors in pathology, behavior and biomarkers and modulation by treatment, sex and ApoE isotype. The SHR- Stroke prone (SHRSP) rat is the most widely studied model for vascular cognitive impairment (VCI) and develop vascular pathology and a compromised neurovascular unit. We used this to create “SHRSPFAD” rats by breeding in mutant APP/PS1 transgenes. Our SHRSPFAD rat shows multiple features of MxD including tauopathy, recently speculated to be increased disproportionately to amyloid in MxD. We propose four aims, which include methods to address limitations of one of the controls: normotensive WKY rats (founder of SHRSP), which is used as the non-hypertensive control, but poses the same limitations as AD models with homozygous colonies (e.g. ApoETR, 3xTg mice etc.), so the aims attempt to overcome this limitations, such as exploring how severity of hypertension affects the synergism between AD and hypertension within phenotype. Aim 1 determines if further increasing hypertension, using high salt diet, used with SHSRP to exacerbate hypertension (and lower VEGF and VGF) affects aging or sex modulation of synergism between AD and hypertension. Aim 2 also addresses this limitation, by reducing hypertension with Angiotensin II Receptor Blockers (ARBs), known to protect the BBB and reduce dementia risk. Thus Aim 2 validates hypertensive-dependent effects on pathology, biomarkers and behavior using ARBs in the SHRSPFAD model. Aims 3 and 4 address effects of ApoE4 the main genetic AD risk factor (notably in women), also impactsing vasculature. Hypertension in post- menopausal female E4 carriers creates a high dementia risk unlike rodents that lack a precipitous drop in antihypertensive and neuroprotective estrogen. Therefore Aim 3: characterizes a novel ApoE SHRSPFAD model and determines the impact of losartan and the anti-estrogen receptors involved in BP control. Since comorbidities in MxD introduce multiple pathways, polypharmacy is necessary in the clinic. Disruption of VEGF signaling is seen in VCI and with ApoE4, so we evaluate the effects of ARB with the FDA approved PPD3 inhibitor Cilostazol, which restores VEGF signaling, protecting the neurovascular unit. Thus, Aim 4 determines efficacy of the combination therapy ARB and Cilostazol. Aims 1-4 variables: vascular- dependent and cognitive variables, bulk and glia- and endothelial-specific RNAseq analysis, tau, Aβ, demyelination, mitochondrial deficits and brain- derived exosomal plasma biomarkers associated with neuroinflammation and disruption of the perivascular unit.

抽象的这项修订的建议利用了我们最近描述的新型混合痴呆模型（MXD）（Denver等。 2019年），最普遍的痴呆症，但MXD受试者通常被排除在广告试验之外。很少具有血管和阿尔茨海默氏症（AD）病理的模型，除了缺乏共识 MXD的神经病理学（或神经精神病学）诊断标准。因此，该建议旨在确定 AD和高血压相关脑血管疾病之间的协同和独立相互作用病理，行为和生物标志物的因素以及通过治疗，性别和APOE同种型调节。 shr- 俯卧（SHRSP）大鼠是血管认知障碍（VCI）的最广泛研究的模型，并发展血管病理学和神经血管单位受损。我们用它来创建“ shrspfad”大鼠突变App/ps1转基因中的育种。我们的Shrspfad大鼠显示了MXD的多个功能 Tauopathy，最近被认为与MXD中的淀粉样蛋白相比不成比例。我们提出了四个目标，其中包括解决其中一个控件局限性的方法：正常的WKY大鼠（SHRSP的创始人），它被用作非高血压控制，但位置与纯合的AD模型相同的局限性殖民地（例如Apoetr，3XTG小鼠等），因此目的试图克服这一局限性，例如探索如何高血压的严重程度会影响表型内AD和高血压之间的协同作用。目标1 确定与SHSRP一起使用高盐饮食的高血压进一步增加的高血压是否加剧了高血压（以及较低的VEGF和VGF）影响AD和高血压之间协同作用的衰老或性别调节。目的 2还通过用血管紧张素II受体阻滞剂（ARB）降低高血压来解决这一局限性保护BBB并降低痴呆症风险。目标2验证了高血压依赖性的影响 SHRSPFAD模型中使用ARB的病理，生物标志物和行为。目标3和4的地址效应 APOE4主要的遗传AD风险因素（尤其是在女性中），也影响脉管系统。高血压更年期女性E4载体会产生高痴呆症风险，与缺乏精确下降的啮齿动物不同抗高血压和神经保护性雌激素。因此AIM 3：表征一种新型的Apoe Shrspfad模型并确定Losartan和涉及BP对照的抗雌激素受体的影响。自合并症以来在MXD中引入了多种途径，在诊所中需要多药。 VEGF信号的破坏是请参阅VCI和APOE4，因此我们通过FDA认可的PPD3抑制剂Cilostazol，评估ARB的影响，恢复VEGF信号传导，保护神经血管单元。这是目标4确定联合疗法ARB和Cilostazol。目标1-4变量：血管依赖和认知变量，批量以及神经胶质和内皮特异性RNASEQ分析，tau，aβ，脱髓鞘，线粒体缺陷和脑衍生的外泌体等离子体生物标志物与神经炎症和血管周期单位的破坏有关。