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

项目2摘要 更年期过渡是中年妇女报告的许多认知障碍的原因。 除了内源性激素的自然损失对认知的不利影响外， 因此，阿尔茨海默病和其他相关痴呆症的患病率在妇女中高于男子， 在45岁时患老年痴呆症的风险增加一倍。激素疗法是最有效的治疗方法 对于伴随更年期的血管扩张和睡眠中断，但干预的时机可能有一个 对整体结果，特别是对认知能力的保护有至关重要的影响。而晚 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 预防认知能力下降，无论是否存在阿尔茨海默病病理。此外，本发明还提供了一种方法， 心血管和代谢并发症与更严重的认知能力下降直接相关， 再加上内源性雌激素的丢失，可能会进一步增加患阿尔茨海默病的风险。 和血管性痴呆虽然已经描述了高血压和代谢疾病损害 神经血管耦合--使局部血液供应与神经元活动相匹配的微调机制--它是 未知神经血管耦合是否被破坏最终导致认知保护的丧失， 雌激素.鉴于神经血管耦联的机制受到内皮细胞一氧化氮的严格调节， 一氧化氮合酶，我们认为心脏代谢合并症会对一氧化氮的可用性产生负面影响， 它消除雌激素诱导的神经保护作用的程度。因此，我们的工作假设是， 绝经前的高血压和代谢性疾病阻碍了激素治疗的有益作用， 通过钝化神经血管耦合来预防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，受损的突触可塑性所需的形成和稳定， 突触需要创建功能性皮层电路，因此认知。我们还将检验假设 增加内皮型一氧化氮合酶活性和一氧化氮生物利用度将消除 在神经血管耦合中。这项研究将确定，预先存在的高血压和肥胖引起的 卵巢切除术前的代谢疾病使中年雌二醇治疗对突触的积极作用无效， 可塑性和突触稳定性，损害皮层回路存储和管理信息的能力， 将确定皮层微电路的改变，负责缺乏经验依赖性突触， 可塑性这项研究还将检查线粒体在破坏神经元活动中的作用，并描述线粒体的特征。 分子机制介导受损的神经血管耦合，这是与损失， 雌激素的神经保护作用专注于我们可以全面研究的皮层回路， 操纵，这项研究将创造基础知识的设计和改进个性化或 精确干预，旨在预防或治疗绝经后妇女的认知障碍， 阿尔茨海默病和血管性痴呆。

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.