Metabolic and Vascular Factors in tau pathogenesis

摘要 该修订的提议利用了我们最近描述的混合型痴呆（MxD）的新模型（Denver et al. 2019），最普遍的痴呆症，但MxD受试者往往被排除在AD试验之外。很少有 同时存在血管和阿尔茨海默病（AD）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，本建议旨在确定 AD与高血压相关脑血管病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同种型的调节。SHR- 卒中易感（SHRSP）大鼠是血管性认知障碍（VCI）研究最广泛的模型， 血管病变和神经血管受损我们用这个来创造“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， 其包括解决对照之一的局限性的方法：血压正常的WKY大鼠（SHRSP的创始者）， 其被用作非高血压对照，但与具有纯合子的AD模型具有相同的局限性。 集落（例如ApoETR、3xTg小鼠等），因此，这些目标试图克服这种局限性，例如探索如何 高血压的严重程度影响AD与高血压表型间的协同作用。要求1 确定使用高盐饮食、与SHSRP联合使用是否会进一步增加高血压 (and降低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也解决了这一局限性，通过用已知的血管紧张素II受体阻滞剂（ARB）降低高血压， 保护血脑屏障，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的病理学、生物标志物和行为。目标3和目标4处理 ApoE 4是主要的遗传性AD风险因素（尤其是女性），也影响血管系统。术后高血压 绝经期女性E4携带者产生高痴呆风险，不像啮齿类动物， 抗高血压和神经保护的雌激素。因此，目的3：表征新的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中引入多个途径，临床上有必要使用多种药物。VEGF信号传导的中断是 在VCI和ApoE 4中观察到，因此我们评估了ARB与FDA批准的PPD 3抑制剂西洛他唑的作用， 恢复VEGF信号，保护神经血管单位。因此，目标4确定了 ARB和西洛他唑联合治疗。目标1-4个变量：血管依赖性和认知变量，批量 和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- 衍生的与神经炎症和血管周围单位破坏相关的外泌体血浆生物标志物。

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.