Metabolic and Vascular Factors in tau pathogenesis

摘要 这项修订的建议利用了我们最近描述的混合性痴呆(MXD)的新模型(Denver等人)。 2019年)，这是最常见的痴呆症，但MXD受试者往往被排除在AD试验之外。有一个稀缺的 血管和阿尔茨海默病(AD)病理共存的模型，此外在 MXD的神经病理学(或神经精神病学)诊断标准。因此，这项提案试图确定 阿尔茨海默病与高血压相关脑血管疾病的协同作用和独立作用 病理、行为和生物标志物中的因素以及治疗、性别和载脂蛋白E同型的调节。SHR- 卒中易感大鼠(SHRSP)是目前研究最多的血管性认知功能障碍(VCI)模型。 血管病理和受损的神经血管单位。我们用这个创造了“SHRSPFAD”大鼠 突变型APP/PS1转基因育种。我们的SHRSPFAD大鼠表现出MXD的多个特征，包括 肌萎缩侧索硬化症，最近推测在MXD中与淀粉样蛋白不成比例地增加。我们提出了四个目标， 其中包括解决其中一个对照组的局限性的方法：血压正常的WKY大鼠(SHRSP的创始人)， 作为非高血压对照，但与纯合子AD模型具有相同的局限性 克隆(例如ApoETR、3xTg小鼠等)，因此AIMS试图克服这一限制，例如探索如何 高血压的严重程度影响AD与高血压在表型上的协同作用。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，以加重高血压 (以及较低的血管内皮生长因子和血管内皮生长因子)影响AD和高血压之间的协同作用的增龄或性别调节。目标 通过使用血管紧张素II受体阻滞剂(ARB)降低高血压，也解决了这一局限性。 保护血脑屏障，降低痴呆症风险。因此，目标2验证了高血压依赖对 SHRSPFAD模型中ARB的病理学、生物标志物和行为。目标3和4针对的是 载脂蛋白E4是阿尔茨海默病的主要遗传危险因素(尤其在女性中)，也会影响血管系统。后高血压- 绝经期雌性E4携带者与啮齿类动物不同，前者患痴呆症的风险较高，后者则不会急剧下降 抗高血压和神经保护的雌激素。因此，目标3：描述一种新的ApoE SHRSPFAD模型 并确定了氯沙坦和参与血压控制的抗雌激素受体的影响。因为共病 在MXD中引入多个途径，临床上多药联用是必要的。血管内皮细胞生长因子信号转导受阻 在VCI和ApoE4中可见，因此我们评估了ARB与FDA批准的PPD3抑制剂西洛他唑的疗效， 恢复血管内皮生长因子信号，保护神经血管单位。因此，目标4决定了 ARB和西洛他唑联合治疗。AIMS 1-4变量：血管依赖变量和认知变量 以及胶质细胞和内皮特异性RNA序列分析、tau、Aβ、脱髓鞘、线粒体缺陷和脑- 衍生的胞外血浆生物标记物与神经炎症和血管周围单位的破坏有关。

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.