Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementia

我们建议研究蛋白酶激活受体(PAR)4在血管认知中的作用。 损害和痴呆症(VCID)。因为创伤性脑损伤是AD的主要危险因素，由创伤引起 血小板活化和凝血酶处于导致纤维蛋白沉积、微梗塞、 血脑屏障破坏和炎症可能导致VCID。PAR4是一种血小板GPCR，它是 被凝血酶强烈激活，仅缓慢失活，因此贡献了大部分来自血小板的 凝血酶，更多促凝血微粒的形成，纤维蛋白沉积增加，以及血小板的启动- 刺激炎症。PAR4也在免疫细胞和血管中表达，在炎症状态下 在这种情况下，PAR4通过PAR4基因F2RL3的表观去甲基化而过表达。PAR4淘汰赛 研究已经确定了PAR4在止血和血栓形成中的作用，以及在中性粒细胞归巢和 血管损伤部位的侵袭。我们已经证明，PAR4在前额叶中的表达水平较高 在纵向人类队列中，老年人的大脑皮层与较快的认知衰退速度有关 评估认知老化、宗教秩序研究(ROS)和快速记忆与衰老项目(MAP)。 我们还发现，在表达一套5个突变的5XFAD小鼠的脑小动脉上，PAR4表达上调 与家族性阿尔茨海默病有关。然而，直接测试PAR4在血管性痴呆和AD病理中的作用 以前从未进行过。在这项资助中，我们将研究PAR4在大脑老化中的作用 患有痴呆症的人以及5XFAD小鼠。在目标1中，我们建议探索PAR4人类的作用 人的遗传变异、死后脑表达和死后脑表观遗传学改变 AD和VCID的神经病理和临床进展。在目标2中，我们将PAR4-/-小鼠与5XFAD小鼠杂交 确定缺乏PAR4是否可以防止纤维蛋白沉积和炎症，并增强认知。在AS中 在长寿/衰老、炎症和免疫、血管疾病和痴呆症等方面都存在性别差异 研究将在男性和女性中进行。如果PAR4的过度表达增加了痴呆的进展，并且 在重度动物模型5XFAD中，PAR4的缺失可以阻止或减缓痴呆的发展，这将 提示对PAR4的药理抑制可能是一种有用的治疗方法，表明 更深入地评价PAR4作为人类的药理靶点。PAR4在一开始的关键作用 血小板活化和引发炎症的级联反应将使其成为极好的治疗靶点 阿尔茨海默病和血管性痴呆。

We propose to study the role of protease-activated receptor (PAR) 4 in contributing to vascular cognitive impairment and dementia (VCID). Because traumatic brain injury is a major risk factor for AD, wounding-induced platelet activation and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption and inflammation that may contribute to VCID. PAR4 is a platelet GPCR that is strongly activated by thrombin and only slowly inactivated, and thus contributes most of the platelet-derived thrombin, greater procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet- stimulated inflammation. PAR4 is also expressed in immune cells and vasculature, and under inflammatory conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3. PAR4 knockout studies have determined a role for PAR4 in hemostasis and thrombosis, as well as in neutrophil homing and invasion at the site of vascular insult. We have shown that higher levels of PAR4 expression in the prefrontal cortex of aging adults were associated with a faster rate of cognitive decline in a longitudinal human cohort evaluating cognitive aging, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). We also found that PAR4 is upregulated on cerebral arterioles in 5XFAD mice that express a suite of 5 mutations associated with familial AD. However, a direct test of the role of PAR4 in vascular dementia and AD pathology has never been carried out previously. In this grant, we will study the role of PAR4 both in the brains of aging humans with dementia as well as in 5XFAD mice. In Aim 1, we propose to explore the role of PAR4 human genetic variation, postmortem brain expression, and postmortem brain epigenetic alterations in the neuropathology and clinical progression of AD and VCID. In Aim 2, we will cross PAR4-/- mice with 5XFAD mice to determine if lack of PAR4 will protect against fibrin deposition and inflammation and enhance cognition. In As sex differences are present in longevity/aging, inflammation and immunity, vascular disease and dementia, all studies will be performed in both sexes. If overexpression of PAR4 increases the progression of dementia, and deletion of PAR4 can arrest or slow the development of dementia in the severe animal model 5XFAD, this will suggest that pharmacological inhibition of PAR4 might be a useful approach therapeutically, suggesting a much more in-depth evaluation of PAR4 as a pharmacological target in humans. A key role of PAR4 at the beginning of the cascade of platelet activation and initiation of inflammation would make it an excellent target for treatment of AD and vascular dementia.