Metabolic syndrome and hippocampal Ca2+ dysregulation in aging memory decline

描述（由申请人提供）：越来越多的流行病学和实验证据表明，与代谢综合征相关的因素，包括葡萄糖失调、胰岛素不敏感和/或肥胖，与衰老的认知能力下降有关。此外，肥胖和代谢综合征的发病率正接近流行病的程度。噻唑烷二酮类（TZD），选择性过氧化物酶体增殖物激活受体- γ (PPAR3)激动剂，改善代谢综合征的几个方面，包括降低2型糖尿病患者的胰岛素抵抗、葡萄糖和胆固醇水平，也与阿尔茨海默病（AD）模型中的炎症和2-淀粉样蛋白负荷减少有关。然而，将外周代谢综合征与脑功能障碍联系起来的机制仍然知之甚少，并且很少有研究分析老年动物的这些外周-脑关系。在过去的几年里，我们和其他人已经发现了相当多的电生理和成像证据，表明海马Ca2+失调与衰老有关认知能力下降。最近，我们的基因微阵列研究也揭示了海马胰岛素和葡萄糖信号的下调与衰老相关的记忆障碍有关。在这里，我们将验证代谢综合征的外周成分通过作用于l型电压门控Ca2+通道（L-VGCCs）、NMDARs、Ca2+诱导的Ca2+释放（CICR）和Ca2+依赖的后超极化（AHP）诱导海马Ca2+稳态改变的工作假设，从而对突触可塑性（LTP）和认知功能产生负面影响。我们还将验证这些作用部分是由脑胰岛素/葡萄糖信号通路的变化介导的，并且可以被TZDs抵消。Specific Aim # 1将研究F344只喂食正常饮食的雄性大鼠，并确定在7-8和18-20月龄时，代谢失调的哪一部分与认知功能和海马电生理/成像功能（L-VGCCs, NMDARs， CICR， AHPs和LTP）的测量最密切相关。Specific Aim #2将测试饮食性肥胖（DIO）是否会加剧大脑衰老的神经生物学、认知、基因表达和神经病理学指标，以及TZDs干预是否可以减缓或逆转这一过程。具体目标#3将分析胰岛素对海马体切片的影响，测试对衰老电生理标记的直接影响，并将测试老年动物神经元表现出胰岛素抵抗的子假设。总之，这些多学科研究将首次系统分析外周代谢综合征变量与脑衰老细胞机制之间的联系。因此，即使中心假设被拒绝，提出的研究也将为代谢综合征的影响以及TZDs对大脑的作用提供更明确的证据。代谢综合征和糖尿病是与年龄和肥胖相关的疾病，在我们的社会中正迅速接近流行病的比例。最近的研究表明，代谢综合征和认知能力下降之间可能存在联系。外周代谢失调的个体成分对脑功能产生负面影响的潜在机制尚不清楚。我们的研究将发现大脑老化、糖尿病和肥胖之间的新联系。如果成功，我们的项目可以通过提供强有力的线索来帮助确定新的治疗靶点和防止衰老的认知能力下降，从而影响公众健康。

DESCRIPTION (provided by applicant): Increasing epidemiological and experimental evidence shows that factors associated with metabolic syndrome, including glucose dysregulation, insulin insensitivity, and/or obesity, are linked to cognitive decline in aging. Moreover, the incidence of obesity and metabolic syndrome are approaching epidemic proportions. The thiazolidinediones (TZD), selective peroxisome proliferator-activated receptor-gamma (PPAR3) agonists, improve several aspects of metabolic syndrome including lowering insulin resistance, glucose and cholesterol levels in Type 2 diabetics, and have also been linked to decreased inflammation and 2-amyloid load in models of Alzheimer's disease (AD). However, the mechanisms that link peripheral metabolic syndrome to brain dysfunction are still poorly understood, and few studies have analyzed these periphery-brain relationships in aged animals. Over the past years, we and others have found considerable electrophysiological and imaging evidence that hippocampal Ca2+ dysregulation with aging correlates with cognitive decline. Recently, our gene microarray studies also revealed downregulation of hippocampal insulin and glucose signaling that correlated with aging-related memory impairment. Here, we will test the working hypothesis that peripheral components of metabolic syndrome induce alterations in Ca2+ homeostasis in the hippocampus by acting on L-type voltage-gated Ca2+ channels (L-VGCCs), NMDARs, Ca2+-induced Ca2+ release (CICR), and the Ca2+-dependent afterhyperpolarization (AHP), thereby negatively affecting synaptic plasticity (LTP) and cognitive function. We will also test the hypothesis that these actions are mediated in part by changes in brain insulin/glucose signaling pathways and can be counteracted by TZDs. Specific Aim # 1 will study F344 male rats fed a normal diet and determine, at 7-8 and 18-20 months of age, which component of metabolic dysregulation most closely associates with measures of cognitive function, and hippocampal electrophysiological/imaging function (L-VGCCs, NMDARs, CICR, AHPs, and LTP). Specific Aim #2 will test whether diet-induced obesity (DIO) exacerbates neurobiological, cognitive, gene expression and neuropathological indices of brain aging and whether interventions with TZDs can slow or reverse this process. Specific Aim #3 will analyze the effects of insulin on hippocampal slices, testing for direct effects on electrophysiological markers of aging, and will test the sub-hypothesis that neurons from aged animals exhibit insulin resistance. Together, these multidisciplinary studies will provide one of the first systematic analyses of links between variables contributing to peripheral metabolic syndrome and cellular mechanisms of brain aging. Therefore, even if the central hypothesis is rejected, the studies proposed will provide more definitive evidence for the impact o metabolic syndrome, as well as the actions of TZDs, on the brain. PUBLIC HEALTH RELEVANCE Metabolic syndrome and diabetes are age- and obesity-related diseases that are rapidly approaching epidemic proportions in our society. Recent studies indicate that there may be a link between metabolic syndrome and cognitive decline. The underlying mechanisms through which individual components of peripheral metabolic dysregulation can negatively impact brain function are not known. Our research will identify new links between brain aging, diabetes and obesity. If successful, our project could impact public health by providing strong clues to help identify novel therapeutic targets and prevent cognitive decline in aging.