Metabolic and Hormonal Mechanisms of VCID

项目摘要/摘要 一半的痴呆症患者有证据表明血管对认知障碍和痴呆症有贡献 (VCID)，要么作为单一病理，要么作为混合性痴呆。糖尿病女性患糖尿病的风险是女性的2.3倍 患VCID的女性多于非糖尿病女性。然而，尽管糖尿病前期会导致认知障碍，而且是3岁 糖尿病前期对VCID的影响知之甚少，是糖尿病的常见程度。更进一步，为什么 代谢性疾病是女性VCID的更大风险因素，目前尚不清楚。女性在这一点上是独一无二的 她们会经历更年期。更年期通过增加患痴呆症的风险，加速了中年痴呆症的风险因素 心血管和代谢性疾病。尽管几乎所有患有VCID的女性都是绝经后， 绝经对VCID的影响是人们认识上的一个重要缺口。这项建议的目的是 了解更年期和糖尿病前期在VCID病理上的重要相互作用，并确定一个 治疗绝经后女性VCID的新方法。我们在小鼠模型中的初步数据 VCID的研究表明，糖尿病前期减少了血流，加速了围产期的认知障碍。 更年期女性，其潜在机制尚不清楚，但可能与神经炎症或 血管损伤；对绝经后女性的影响尚未评估。在绝经后的女性中， 雌激素的主要来源是通过芳香酶在多种组织中局部合成17-β雌二醇。 纸巾。患有其他形式脑溢血的女性脑部芳香酶和脑雌二醇水平显著降低 然而，芳香酶在VCID中的作用尚不清楚。我们已经发现，抑制 芳香化酶对雌性小鼠脑血管功能的严重损害提示靶向芳香化酶在雌性小鼠中的作用 女性可能是增加大脑血流量的有效策略，从而减少VCID的病理。 我们假设糖尿病前期引起的大脑低灌流、认知障碍和神经炎症 在绝经后的女性中会加剧，并将通过增加脑源性激素的产生而逆转 雌二醇。在目标1中，使用VCID的小鼠模型，我们将确定更年期是否会加剧大脑 糖尿病前期引起的低灌注率、神经炎症和认知障碍。在目标2中，我们将确定是否 血管内皮细胞或星形胶质细胞芳香酶的缺失会导致脑低灌流，并加剧认知障碍 绝经后雌性小鼠的神经炎症。在目标3中，我们将确定是否增加雌二醇 尤其是在大脑中改善血管功能，减少认知障碍和神经炎症 糖尿病前期绝经后雌性小鼠。我们预计这些研究将提供机械性的见解， 通过确定治疗VCID的新方法，促进未来的干预措施以减轻痴呆症的负担 绝经后女性：脑部雌二醇量增加。对更年期的影响一无所知 在糖尿病前期女性的VCID方面，开发治疗这一高危人群的治疗方法仍然不太可能。

PROJECT SUMMARY/ABSTRACT Half of all dementia patients have evidence of vascular contributions to cognitive impairment and dementia (VCID), either as a single pathology or as a mixed dementia. Diabetic women have a 2.3-fold greater risk to develop VCID than non-diabetic women. However, even though prediabetes causes cognitive deficits and is 3 times more common than diabetes, little is known regarding the effects of prediabetes on VCID. Further, why metabolic disease is a larger risk factor for VCID in women than in men is unknown. Women are unique in that they go through menopause. Menopause accelerates mid-life risk factors for dementia, by increasing risk for cardiovascular and metabolic diseases. Despite the fact that nearly all women with VCID are post-menopausal, the influence of menopause on VCID is a critical gap in knowledge. The objective of this proposal is to understand the important interaction between menopause and prediabetes on VCID pathology and identify a novel therapeutic approach to treat VCID in post-menopausal females. Our preliminary data in a mouse model of VCID demonstrate that prediabetes reduces blood flow and accelerates cognitive deficits in peri- menopausal females, the underlying mechanism is unknown but may be related to neuroinflammation or vascular damage; effects in post-menopausal females have not been assessed. In post-menopausal women, the major source of estrogen is local synthesis of 17-β estradiol by the enzyme aromatase in a variety of tissues. Brain aromatase and brain estradiol levels are drastically decreased in women with other forms of dementia, however, the role of aromatase in VCID has yet to be explored. We have discovered that inhibition of aromatase severely impairs cerebrovascular function in female mice suggesting that targeting aromatase in females may be an effective strategy for increasing blood flow to the brain, thereby reducing VCID pathology. We hypothesize that cerebral hypoperfusion, cognitive deficits, and neuroinflammation induced by prediabetes will be exacerbated in post-menopausal females and will be reversed by increasing production of brain-derived estradiol. In Aim 1, using a mouse model of VCID, we will determine if menopause exacerbates cerebral hypoperfusion, neuroinflammation, and cognitive deficits induced by prediabetes. In Aim 2, we will determine if loss of endothelial or astrocytic aromatase causes cerebral hypoperfusion and exacerbates cognitive deficits and neuroinflammation in post-menopausal female mice. In Aim 3, we will determine if increasing estradiol specifically in the brain improves vascular function and reduces cognitive deficits and neuroinflammation in prediabetic post-menopausal female mice. We anticipate these studies will provide mechanistic insight that will facilitate future interventions to decrease the burden of dementia by identifying a novel approach to treat VCID in post-menopausal females: enhancement of brain estradiol. Without knowledge of the effects of menopause on VCID in prediabetic females, development of therapies to treat this high-risk population remains unlikely.