Metabolic and Hormonal Mechanisms of VCID

项目总结/摘要 所有痴呆患者中有一半有证据表明血管对认知障碍和痴呆有贡献 （VCID），作为单一病理或作为混合性痴呆。糖尿病女性患糖尿病的风险是男性的2.3倍。 比非糖尿病女性更易发生VCID。然而，即使糖尿病前期导致认知缺陷， 糖尿病比糖尿病常见两倍，但关于糖尿病前期对VCID的影响知之甚少。更进一步说，为什么 代谢性疾病是女性VCID的一个比男性更大的危险因素尚不清楚。女人是独一无二的 她们会经历更年期更年期通过增加老年痴呆症的风险， 心血管和代谢疾病。尽管几乎所有患有VCID的女性都是绝经后的， 绝经对VCID的影响是一个关键的知识空白。这项建议的目的是 了解绝经和糖尿病前期对VCID病理的重要相互作用，并确定一个 治疗绝经后女性VCID的新治疗方法。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量，加速了糖尿病患者的认知缺陷， 绝经期女性，其潜在机制尚不清楚，但可能与神经炎症或 血管损伤;尚未评估对绝经后女性的影响。在绝经后的妇女中， 雌激素的主要来源是在各种组织中通过芳香酶局部合成17-β雌二醇。 组织中在患有其他形式的乳腺癌的女性中，脑芳香化酶和脑雌二醇水平急剧下降。 然而，在痴呆中，芳香化酶在VCID中的作用还有待探索。我们发现抑制 芳香化酶严重损害了雌性小鼠的脑血管功能，这表明靶向芳香化酶， 女性可能是一个有效的策略，增加血液流向大脑，从而减少VCID病理。 我们假设糖尿病前期引起的脑灌注不足、认知缺陷和神经炎症 将在绝经后女性中加剧，并将通过增加脑源性 雌二醇在目标1中，我们将使用VCID小鼠模型，确定绝经是否会加重脑血管疾病， 低灌注、神经炎症和糖尿病前期诱导的认知缺陷。在目标2中，我们将确定 内皮细胞或星形胶质细胞芳香化酶的缺失导致脑灌注不足并加重认知缺陷 以及绝经后雌性小鼠的神经炎症。在目标3中，我们将确定增加雌二醇 特别是在大脑中改善血管功能，减少认知缺陷和神经炎症， 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，以减少痴呆症的负担 绝经后女性：脑雌二醇增加。如果不知道更年期的影响 在糖尿病前期女性的VCID上，治疗这种高危人群的疗法的开发仍然是不可能的。

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.