Impact of hypertension and high-fat diet on mechanisms by which estradiol affects cortical synaptic plasticity.

项目2摘要 更年期转变是女性在中年报告的许多认知障碍的原因。 除了内源性激素自然丧失对认知的有害影响外，可能还有 结果，阿尔茨海默病和其他相关痴呆的患病率在女性中高于男性， 在45岁时罹患阿尔茨海默氏症的风险是常人的两倍。激素疗法是最有效的治疗方法。 对于伴随绝经而来的血管运动和睡眠障碍，但干预的时机可能会有 对总体结果，特别是对认知能力的保存有至关重要的影响。而迟到了 激素治疗干预没有好处，甚至可能是有害的，早期干预似乎赋予了 防止认知能力下降，无论是否存在阿尔茨海默病的病理。此外, 心血管和新陈代谢并发症与认知能力下降直接相关， 再加上内源性雌激素的丧失，可能会进一步增加患阿尔茨海默病的风险 和血管性痴呆症。虽然已经描述了高血压和代谢性疾病会损害 神经血管偶联--将局部血液供应与神经元活动相匹配的微调机制--是 尚不清楚神经血管偶联是否中断是认知保护丧失的最终原因 雌激素。鉴于调控神经血管偶联的机制受到内皮一氧化氮的严格调控 一氧化氮合酶，我们认为心脏代谢合并症对一氧化氮的有效性有负面影响 在多大程度上取消雌激素诱导的神经保护。因此，我们的工作假设是 绝经前高血压和代谢性疾病阻碍激素治疗的有益效果 通过钝化神经血管偶联来防止与衰老相关的认知能力下降。这会导致局部受损 网络活动，因此，与突触可塑性受损有关，而突触可塑性是形成和稳定 突触需要创造功能性的皮质回路，因此也是认知所必需的。我们还将检验这一假设 增加内皮型一氧化氮合酶活性和一氧化氮的生物利用度将消除这些缺陷 在神经血管耦合中。这项研究将确定高血压和肥胖的先天存在 卵巢切除前的代谢性疾病抵消了中年雌激素治疗对突触的积极影响 可塑性和突触稳定，损害皮质回路存储和管理信息的能力，以及 将确定皮层微电路中导致经验依赖型突触缺陷的变化 可塑性。这项研究还将研究线粒体在神经元活动中断中的作用，并表征 介导神经血管偶联受损的分子机制与血管紧张素转换酶缺失有关 雌激素的神经保护作用。聚焦于我们可以全面研究和研究的大脑皮层回路 这项研究将为个性化产品的设计和改进创造基础知识 旨在预防或治疗有高血压风险的绝经后妇女认知障碍的精确干预措施 阿尔茨海默氏症和血管性痴呆。

Project 2 Summary The menopausal transition is responsible for many of the cognitive impairments reported by women at midlife. In addition to the detrimental effects of the natural loss of endogenous hormones on cognition, and as a probable consequence, the prevalence of Alzheimer’s disease and other related dementias is higher in women than men, with double the lifetime risk of Alzheimer’s disease at age 45. Hormone therapy is the most effective treatment for the vasomotor and sleep disruptions that accompany menopause, but timing of the intervention may have a crucial impact on overall outcome, particularly on the preservation of cognitive capabilities. Whereas late hormone therapy interventions have no benefit, or may even be harmful, early interventions seem to bestow protection against cognitive decline, regardless of the presence of Alzheimer’s disease pathology. In addition, cardiovascular and metabolic complications are directly associated with sharper cognitive decline, which together with the loss of endogenous estrogens, may further increase the risk of developing Alzheimer’s disease and vascular dementia. While it has been described that hypertension and metabolic disease impair neurovascular coupling—the fine-tuned mechanism that matches local blood supply with neuronal activity—it is unknown if disrupted neurovascular coupling is ultimately responsible for the loss of cognitive protection by estrogen. Given that the mechanisms governing neurovascular coupling are tightly regulated by endothelial nitric oxide synthase, we believe that cardiometabolic comorbidities negatively impact the availability of nitric oxide to the extent that it abolishes the estrogen-induced neuroprotection. Therefore, our working hypothesis is that hypertension and metabolic disease prior to menopause impede the beneficial effects of hormone therapy in preventing aging-related cognitive decline by blunting neurovascular coupling. This leads to impaired local network activity, and therefore, to impaired synaptic plasticity required for the formation and stabilization of synapses needed to create functional cortical circuits and therefore for cognition. We will also test the hypothesis that increasing endothelial nitric oxide synthase activity and nitric oxide bioavailability will eliminate the deficits in neurovascular coupling. This study will determine that the preexistence of hypertension and obesity-induced metabolic disease prior to ovariectomy nullifies the positive effects of midlife estradiol treatment on synaptic plasticity and synaptic stabilization, impairing the ability of cortical circuits to store and manage information, and will identify alterations in the cortical microcircuitry responsible for the deficient experience-dependent synaptic plasticity. The study will also examine the role of mitochondria in disrupted neuronal activity and characterize the molecular mechanisms mediating the impaired neurovascular coupling that is associated with the loss of estrogen’s neuroprotective effects. Focusing on a cortical circuit that we can comprehensively study and manipulate, this study will create foundational knowledge for the design and improvement of personalized or precision interventions aimed to prevent or treat cognitive disturbances in postmenopausal women at risk for Alzheimer’s disease and vascular dementia.