Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementia

我们拟研究蛋白酶激活受体（PAR）4在血管性认知功能中的作用， 痴呆症（VCID）。由于创伤性脑损伤是AD的主要危险因素， 血小板活化和凝血酶是导致纤维蛋白沉积，微梗塞， 可能导致VCID的血脑屏障破坏和炎症。PAR 4是血小板GPCR， 凝血酶强烈激活，只有缓慢失活，因此有助于大部分血小板衍生的 凝血酶、更大的促凝血微粒形成、增加的纤维蛋白沉积和血小板活化的起始。 刺激炎症。PAR 4还在免疫细胞和脉管系统中表达，并且在炎症条件下表达。 在某些条件下，PAR 4通过PAR 4基因F2 RL 3的表观遗传去甲基化而过表达。PAR 4基因敲除 研究已经确定了PAR 4在止血和血栓形成中的作用，以及在中性粒细胞归巢和 在血管损伤部位的侵入。我们已经证明，在前额叶中PAR 4表达水平较高， 在一项纵向人类队列研究中，老年人的大脑皮层与认知能力下降的速度更快有关 评估认知老化，宗教秩序研究（ROS）和拉什记忆和老化项目（MAP）。 我们还发现PAR 4在表达一系列5个突变的5XFAD小鼠的脑小动脉中上调 与家族性AD有关。然而，PAR 4在血管性痴呆和AD病理学中的作用的直接测试 从来没有进行过。在这项资助中，我们将研究PAR 4在衰老大脑中的作用， 在患有痴呆症的人类以及5XFAD小鼠中。在目的1中，我们提出探索PAR 4在人类中的作用。 遗传变异，死后脑表达，死后脑表观遗传改变， AD和VCID的神经病理学和临床进展。在目标2中，我们将PAR 4-/-小鼠与5XFAD小鼠杂交， 以确定缺乏PAR 4是否会防止纤维蛋白沉积和炎症并增强认知能力。就任 性别差异存在于长寿/衰老、炎症和免疫、血管疾病和痴呆等方面， 研究将在两性中进行。如果PAR 4的过度表达增加痴呆的进展， PAR 4的缺失可以阻止或减缓严重动物模型5XFAD中痴呆的发展，这将 表明PAR 4药理学抑制可能是治疗上有用的方法， 对PAR 4作为人体药理学靶点进行更深入的评估。PAR 4在初期的关键作用 血小板活化级联反应和炎症的启动将使其成为一个很好的治疗目标 AD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.