Age-related Hypertension and Vascular Cognitive Impairment

摘要 高血压是脑小血管疾病发展的关键危险因素， 血管性认知障碍，这是继阿尔茨海默氏病之后第二大常见的痴呆症原因。 越来越多的证据表明，血脑屏障功能障碍和神经炎症在脑缺血中起着关键作用。 高血压的病理生理学，并有助于血管性认知障碍的发展。而 血管紧张素II 1型受体拮抗剂是治疗高血压的一线疗法， 改善神经认知功能。考虑到美国每年治疗痴呆症的费用， 到2040年，高血压的患病率将从20-44岁美国成年人的46%上升到78%以上。 65岁以上的成年人，绝经后高血压发病率急剧增加， 关键的公共卫生需要更好地了解性别、年龄依赖性和性别之间的机械联系， 高血压和血管性认知障碍。这个应用程序将测试的全球假设，正常 衰老引起性依赖性高血压，导致中枢微血管损伤和神经炎症， 引起血管性认知障碍，其可通过血管紧张素II 1型受体拮抗剂改善。 我们的目的将在雄性和雌性3月龄、8月龄和16月龄的Sprague-Dawley大鼠（哺乳动物模型）中进行。 正常老化）。以下特定目的将检验该假设：特定目的1：下丘脑PVN血液 脑屏障功能障碍和神经炎症通过可逆性高血压， 性别依赖性血管紧张素II 1型受体机制。具体目标2：血压依赖性高血压 诱发性海马微血管损伤和神经回路功能障碍驱动血管性认知障碍 通过可逆的性别依赖性血管紧张素II 1型受体机制。我们的创新方法直接 与NIA治疗阿尔茨海默病及其相关痴呆症的目标一致， 提供新的见解的基本机制，有助于性别和年龄依赖性高血压- 驱动的血管性认知障碍，完全符合PAR-19-070和NOT-AG-20-038的目的。具体 目的1将建立下丘脑PVN血脑屏障功能障碍和神经炎症有助于 年龄依赖性高血压的发展，通过可逆的 性别依赖性血管紧张素II 1型受体机制。具体目标2将确定年龄依赖性 高血压诱发的海马微血管损伤和神经回路功能障碍驱动血管认知 通过可逆性性别依赖性血管紧张素II 1型受体机制的损伤。我们的创新 方法将直接调查事件的性别依赖性机制后遗症和潜在的神经 PVN和海马两者的功能障碍与年龄相关，并且可能导致年龄- 依赖性高血压导致的血管性认知障碍

ABSTRACT Hypertension is a key risk factor for the development of cerebral small vessel disease, the foremost source of vascular cognitive impairment which is the second most common cause of dementia after Alzheimer’s disease. There is increasing evidence that blood brain barrier dysfunction and neuroinflammation play a pivotal role in the pathophysiology of hypertension and contribute to the development of vascular cognitive impairment. While Angiotensin II Type 1 receptor antagonists are first line therapy to treat hypertension they have recently been demonstrated to improve neurocognitive function. Given the annual cost of dementia in the US is expected to double by 2040, the prevalence of hypertension rises from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65, and that hypertension incidence increases dramatically post-menopause there is a critical public health need for a greater understanding of the mechanistic link(s) between sex, age-dependent hypertension and vascular cognitive impairment. This application will test the global hypothesis that normal aging evokes sex-dependent hypertension that drives central microvascular injury and neuroinflammation to cause vascular cognitive impairment which can be ameliorated by Angiotensin II Type 1 receptor antagonism. Our Aims will be conducted in male and female 3-, 8-, and 16-month-old Sprague-Dawley rats (model of normal aging). The following Specific Aims will test this hypothesis: Specific Aim 1: Hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to age-dependent hypertension via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2: Age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach is directly aligned with NIA Stratetgic Goals that address Alzheimer's disease and its related dementias and is designed to provide novel insights into the basic mechanisms contributing to sex- and age-dependent hypertension- driven vascular cognitive impairment and fully meets the intent of PAR-19-070 and NOT-AG-20-038. Specific Aim 1 will establish that hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to the development of age-dependent hypertension, which drives vascular cognitive impairment, via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2 will establish that age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach will directly investigate the sex dependent mechanistic sequelae of events and underlying neural dysfunction in both the PVN and hippocampus that is associated with, and perhaps contributing to, age- dependent hypertension-driven vascular cognitive impairment.