Metabolic and Vascular Factors in tau pathogenesis

tau 发病机制中的代谢和血管因素

• 批准号: 10615154
• 负责人: SALLY ANN FRAUTSCHY
• 金额: $ 67.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/10615154
• 关键词: 3xTg-AD mouse; APP-PS1; Acceleration; Address; Adverse effects; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' 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; Exclusion; 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; behavioral phenotyping; blood pressure control; cell type; cohort; comorbidity; dementia risk; diagnostic criteria; drug efficacy; efficacy evaluation; epidemiology study; exosome; experience; high salt diet; human female; hypertensive; improved; inhibitor; male; men; mixed dementia; mutant; neuroimaging; neuroinflammation; neuropathology; neuroprotection; 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

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 该修订后的提案利用了我们最近描述的混合性痴呆 (MxD) 的新颖模型（Denver 等人，2017）。 2019），最常见的痴呆症，但 MxD 受试者经常被排除在 AD 试验之外。有少量 血管和阿尔茨海默病 (AD) 病理共存的模型，除了在以下方面缺乏共识之外 MxD 的神经病理学（或神经精神病学）诊断标准。因此，本提案旨在确定 AD与高血压相关脑血管疾病之间的协同和独立相互作用 病理学、行为和生物标志物的因素以及治疗、性别和 ApoE 同型的调节。 SHR- 易中风（SHRSP）大鼠是血管性认知障碍（VCI）研究最广泛的模型，并发展 血管病理学和受损的神经血管单位。我们用它来创建“SHRSPFAD”大鼠 突变 APP/PS1 转基因育种。我们的 SHRSPFAD 大鼠显示出 MxD 的多种特征，包括 tau 蛋白病，最近推测在 MxD 中与淀粉样蛋白不成比例地增加。我们提出四个目标， 其中包括解决其中一种对照的局限性的方法：血压正常的 WKY 大鼠（SHRSP 的创始人）， 用作非高血压对照，但与纯合 AD 模型具有相同的局限性 菌落（例如 ApoETR、3xTg 小鼠等），因此目标试图克服这一限制，例如探索如何 高血压的严重程度影响表型内 AD 和高血压之间的协同作用。目标1 确定是否进一步增加高血压，使用高盐饮食，与SHSRP一起使用会加剧高血压 （以及较低的 VEGF 和 VGF）影响衰老或 AD 与高血压之间协同作用的性别调节。目的 2 还通过使用已知的血管紧张素 II 受体阻滞剂 (ARB) 降低高血压来解决这一限制 保护血脑屏障并降低痴呆风险。因此，目标 2 验证了高血压依赖性效应 在 SHRSPFAD 模型中使用 ARB 进行病理学、生物标志物和行为。目标 3 和 4 解决以下问题的影响 ApoE4 是 AD 的主要遗传风险因素（尤其是女性），也会影响脉管系统。术后高血压 与啮齿类动物不同，更年期雌性 E4 携带者患痴呆症的风险很高，而啮齿类动物的痴呆症风险没有急剧下降。 抗高血压和神经保护雌激素。因此目标 3：表征新颖的 ApoE SHRSPFAD 模型 并确定氯沙坦和参与血压控制的抗雌激素受体的影响。由于合并症 在MxD中引入多种途径，临床上需要联合用药。 VEGF 信号传导的破坏是 在 VCI 和 ApoE4 中观察到，因此我们评估 ARB 与 FDA 批准的 PPD3 抑制剂西洛他唑的效果， 恢复 VEGF 信号传导，保护神经血管单元。因此，目标 4 决定了 联合治疗ARB和西洛他唑。目标 1-4 变量：血管相关变量和认知变量，批量 以及神经胶质细胞和内皮细胞特异性 RNAseq 分析、tau、Aβ、脱髓鞘、线粒体缺陷和脑- 衍生的外泌体血浆生物标志物与神经炎症和血管周围单位的破坏相关。