Endocrine Regulation of Alcohol Intake

项目摘要/摘要 阿尔茨海默病是一种以认知障碍为特征的进行性神经退行性脑病 功能。阿尔茨海默病是导致痴呆症的最常见原因，据估计，美国有580万人 2020年，65岁及以上的美国人患有阿尔茨海默氏症(alz.org)。淀粉样蛋白积聚 β(Aβ)是一种错误折叠的蛋白质，是阿尔茨海默病的关键病理标志，但也是候选药物 针对Aβ通路的研究收效甚微[1]。最近，新陈代谢的变化，特别是葡萄糖 新陈代谢已被确认为阿尔茨海默病的共同特征[2，3]。值得注意的是， 大约80%的阿尔茨海默病患者表现出糖耐量受损[4]。这些 观察和其他流行病学数据一起导致了这样的假设，即阿尔茨海默病可能会在 部分，是代谢紊乱[3，5]。成纤维细胞生长因子21(FGF21)是一种能纠正 在动物模型中代谢功能障碍和逆转糖尿病和肥胖[6]。FGF21是一个重要的调节因子 是一种有效的胰岛素增敏剂。对FGF21模拟物的临床试验也 证明了靶向这一途径以改善人类代谢特征的有效性[7]。有趣的是， 最近的数据表明，FGF21的应用也可以防止神经退行性变和病理 阿尔茨海默病动物模型的缺陷[11-13]。而循环中的FGF21水平主要由 肝脏[14]，我们的初步数据揭示了一个意想不到的发现，FGF21也在一个非常 中枢神经系统的特定区域。具体地说，FGF21在脾后皮质和 可以向海马体发出信号，并可以调节学习和记忆。先前的一项研究表明 FGF21是由神经元对线粒体压力的反应而诱导的[9]，我们假设FGF21的诱导 在这个区域调节新陈代谢过程，以防止神经退化。有几行证据表明 在长期的代谢损伤中，FGF21的内源性信号可能受损，导致 “FGF21抗性状态”[15]。重要的是，给药水平的FGF21足以 克服这种阻力，恢复代谢平衡[16]。在这项提案中，我们试图探索是否 内源性FGF21信号在阿尔茨海默病进展和恢复过程中也受到损害 通过药理作用FGF21或局部诱导FGF21 持续的腺相关病毒传递，足以减轻认知和病理障碍 阿尔茨海默病小鼠模型。总而言之，这些研究将提供对这种潜力的更好理解 治疗阿尔茨海默病及其相关痴呆的治疗方法。

Project Summary / Abstract Alzheimer's disease is a progressive neurodegenerative brain disease characterized by impairment in cognitive function. Alzheimer's disease is the most common cause of dementia and an estimated 5.8 million people in the United States age 65 and older are living with Alzheimer's dementia in 2020 (alz.org). Accumulation of amyloid beta (Aβ), a misfolded protein, is a key pathological hallmark of Alzheimer's disease but drug candidates targeting Aβ pathways have yielded little success [1]. More recently, changes in metabolism, particularly glucose metabolism, have been identified as a common feature observed in Alzheimer's disease [2, 3]. Notably, approximately 80% of patients with Alzheimer's disease exhibit impairments in glucose tolerance [4]. These observations along with other epidemiological data have led to the postulation that Alzheimer's disease may, in part, be a metabolic disorder [3, 5]. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that corrects metabolic dysfunction and reverses diabetes and obesity in animal models [6]. FGF21 is an important regulator of glucose homeostasis and is a potent insulin sensitizer. Clinical trials with FGF21 mimetics have also demonstrated the efficacy of targeting this pathway to improve metabolic profiles in humans [7]. Interestingly, recent data suggests that FGF21 administration may also prevent neurodegeneration [8-10] and pathological deficits in animal models of Alzheimer's disease [11-13]. While circulating FGF21 levels are derived primarily by the liver [14], our preliminary data reveals the unexpected discovery that FGF21 is also expressed in a very specific region of the central nervous system. Specifically, FGF21 is expressed in the retrosplenial cortex and can signal to the hippocampus and can regulate learning and memory. A previous study demonstrates that FGF21 is induced from neurons in response to mitochondrial stress [9], and we hypothesize that FGF21 induction in this region regulates metabolic processes to prevent neurodegeneration. Several lines of evidence suggest that during prolonged metabolic impairments, endogenous signaling of FGF21 may be impaired leading to a “FGF21 resistant state” [15]. Importantly, administration of pharmacological levels of FGF21 is sufficient to overcome this resistance and restore metabolic homeostasis [16]. In this proposal, we seek to explore whether endogenous FGF21 signaling is also impaired during Alzheimer's disease progression and whether restoration of central FGF21 signaling, via pharmacological administration of FGF21 or local induction of FGF21 via sustained adeno-associated viral delivery, is sufficient to attenuate the cognitive and pathological deficits in a mouse model of Alzheimer's disease. Together, these studies will provide a better understanding of this potential therapeutic approach to treat Alzheimer's Disease and its related dementias.