5-HT 2C Receptor and Alzheimer's Disease

项目摘要 由于全球人口老龄化，阿尔茨海默病（AD）正在达到流行病的程度， 巨大的社会和经济负担。虽然AD最显著的症状是严重的记忆丧失， AD患者还患有神经精神症状，包括社交能力和攻击性受损， 这对这些患者的护理提出了重大挑战。不幸的是， 在AD发病过程中这些神经精神缺陷的基础仍然是完全理解的， 有效的治疗是有限的。脑5-羟色胺（5-HT，血清素）调节多种 生理功能，包括控制愤怒、攻击性、情绪和认知。有趣的是， 许多研究报道，AD患者的大脑显示出广泛的“5-HT去神经支配”， 表现为5-HT神经元数量减少或5-HT生物利用度降低。这表明受损的大脑 5-HT信号传导有助于某些AD症状。我们发现了几个功能丧失的点突变， 编码5-HT 2C受体（5-HT 2CR）的人HTR 2C基因，来自具有认知缺陷的个体， 社交无能我们建立了一个敲入小鼠模型，Htr 2cF 327 L，以模拟一个这样的突变， 发现这些突变小鼠重现了人类的症状，包括记忆力受损， 社交能力和攻击性增强。考虑到Htr 2cF 327 L诱导的表型与 我们测试了氯卡色林（一种选择性5-HT 2CR激动剂）在淀粉样蛋白前体中的作用， AppNL-G-F敲入AD小鼠模型。有趣的是，氯卡色林改善认知和神经精神 在AppNL-G-F小鼠中的缺陷，与腹侧海马CA 1（vCA 1）的神经可塑性增强相关。 这些发现导致了一个普遍的假设，即5-HT/5-HT 2CR信号转导改善了认知和神经功能。 AD中的社会行为为了验证这一假设，我们将首先将联合收割机结合逆行化学遗传学和 功能丧失或获得小鼠模型，以确定5-HT→ vCA 1回路在认知中的作用， 社交性和攻击性以及AD发病机制。使用位点特异性基因操作和 人源化遗传小鼠模型，我们还将确定vCA 1 5-HT 2CRs在认知、社交 攻击性与AD发病机制的关系。最后，我们将测试氯卡色林在两个临床前AD中的作用。 模型（具有不同的致病机制）：AppNL-G-F和PS19。重要的是，我们将测试这些小鼠， 沿着疾病进展的不同年龄，以确定这种药理学作用的关键时间窗。 战略是最有效的。从这些研究中获得的结果有望推动我们的研究。 了解认知/社会行为的基础生物学和人类的神经生物学 AD进展。此外，这些研究具有重要的翻译价值，并将提供一个框架 新的治疗策略，以改善认知和神经精神症状的AD。

PROJECT SUMMARY Owing to the aging of populations worldwide, Alzheimer’s disease (AD) is reaching epidemic proportions, with a large social and economic burden. While the most notable symptom of AD is the severe memory loss, patients with AD also suffer from neuropsychiatric symptoms, including impaired sociability and aggression, which represent significant challenges to the care for these patients. Unfortunately, the mechanisms underlying these neuropsychiatric deficits during AD pathogenesis remain to be fully understood and effective treatments are limited. The brain 5-hydroxytryptamine (5-HT, serotonin) regulates multiple physiological functions, including the control of anger, aggression, mood and cognition. Interestingly, numerous studies reported that the brains of AD patients display extensive “5-HT denervation”, as demonstrated by reduced 5-HT neuron numbers or 5-HT bioavailability. These suggest that impaired brain 5-HT signaling contributes to certain AD symptoms. We identified several loss-of-function point mutations in the human HTR2C gene, encoding 5-HT 2C receptor (5-HT2CR), from individuals with cognitive deficits and social incompetence. We generated a knock-in mouse model, Htr2cF327L, to mimic one such mutation and found that these mutant mice recapitulate human symptoms, including impaired memory, decreased sociability and increased aggression. Given the similarity between the Htr2cF327L-induced phenotypes and those seen in AD, we tested effects of lorcaserin (a selective 5-HT2CR agonist) in an amyloid precursor AppNL-G-F knock-in AD mouse model. Interestingly, lorcaserin ameliorates cognitive and neuropsychiatric deficits in AppNL-G-F mice, associated with enhanced neural plasticity in the ventral hippocampal CA1 (vCA1). These findings led to a general hypothesis that the 5-HT/5-HT2CR signaling ameliorates cognitive and social behaviors in AD. To test this hypothesis, we will first combine the retrograde chemogenetics and loss- or gain-of-function mouse models to determine the role of the 5-HT→vCA1 circuit in cognition, sociability and aggression in health and AD pathogenesis. Using site-specific gene manipulation and the humanized genetic mouse models, we will also determine the role of vCA1 5-HT2CRs in cognition, sociability and aggression in health and AD pathogenesis. Finally, we will test lorcaserin effects in two pre-clinical AD models (with distinct pathogenic mechanisms): AppNL-G-F and PS19. Importantly, we will test these mice at various ages along the disease progression to determine the crucial time window for this pharmacological strategy to be most effective. Results obtained from these studies are expected to advance our understanding about the fundamental biology of cognitive/social behaviors and the neurobiology of human AD progression. In addition, these studies carry significant translational values and will provide a framework for novel therapeutic strategies to ameliorate cognitive and neuropsychiatric symptoms in AD.