5-HT 2C Receptor and Alzheimer's Disease

5-HT 2C 受体与阿尔茨海默病

• 批准号: 10732703
• 负责人: YONG XU
• 金额: $ 55.84万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732703
• 关键词: Age; Aggressive behavior; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Anger; Area; Biological Availability; Biology; Brain; Cognition; Cognitive; Cognitive deficits; Denervation; Disease Progression; Economic Burden; Epidemic; Genes; Genetic; Health; Hippocampus; Human; Impaired cognition; Impairment; Individual; Knock-in; Knock-in Mouse; Memory Loss; Memory impairment; Midbrain structure; Modeling; Moods; Mus; Mutant Strains Mice; Mutation; Neurobehavioral Manifestations; Neurobiology; Neuronal Plasticity; Neurons; Pathogenesis; Pathogenicity; Patient Care; Phenotype; Physiological; Pilot Projects; Point Mutation; Population; Receptor Signaling; Regulation; Reporting; Research; Role; Serotonin; Signal Transduction; Site; Social Behavior; Symptoms; Testing; Therapeutic Intervention; Time; brain dysfunction; effective therapy; gain of function; genetic approach; genetic manipulation; improved; loss of function; mouse model; neuropsychiatric symptom; neuropsychiatry; novel therapeutic intervention; overexpression; pharmacologic; pre-clinical; receptor; serotonin receptor; social; targeted treatment; tau-1

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.

项目摘要 由于全球人口的老龄化，阿尔茨海默氏病（AD）达到了流行比例， 庞大的社会和经济伯恩。虽然广告的最显着症状是严重的记忆丧失，但 AD患者还患有神经精神症状，包括社交性和侵略性， 这代表了这些患者护理的重大挑战。不幸的是，机制 在AD发病机理期间这些神经精神辩护的基础尚待充分理解和 有效的治疗是有限的。大脑5-羟色胺（5-HT，5-羟色胺）调节多个 身体功能，包括控制愤怒，侵略性，情绪和认知。有趣的是， 大量研究报告说，AD患者的大脑显示出广泛的“ 5-HT神经保护”，如 通过降低的5-HT神经元数或5-HT生物利用度证明。这些表明大脑受损 5-HT信号传导有助于某些AD症状。我们确定了几个功能丧失点突变 来自认知缺陷和 社会无能。我们生成了一个敲入的小鼠模型Htr2CF327L，以模仿一个这种突变和 发现这些突变小鼠概括了人类症状，包括记忆力受损，减少了 社交和进取的侵略性。鉴于HTR2CF327L诱导的表型与 在AD中看到的那些，我们测试了lorcasein（一种选择性5-HT2CR激动剂）在淀粉样前体中的效果 AppNL-G-F敲门广告鼠标模型。有趣的是，洛杉矶可以改善认知和神经精神病学 APPNL-G-F小鼠的缺陷，与腹侧海马CA1的神经可塑性增强有关（VCA1）。 这些发现导致了一个普遍的假设，即5-HT/5-HT2CR信号传导可以改善认知和 广告中的社会行为。为了检验这一假设，我们将首先结合逆行化学遗传学和 损失或功效的小鼠模型确定5-HT→VCA1电路在认知中的作用， 社交和健康和广告发病机理的积极性。使用特定于位点的基因操纵和 人性化的遗传小鼠模型，我们还将确定VCA1 5-HT2CR在认知中的作用 并在健康和AD发病机理方面具有侵略性。最后，我们将在两个临床前广告中测试洛杉矶效应 模型（具有不同的致病机制）：AppNL-G-F和PS19。重要的是，我们将在 沿疾病进展的各种年龄，以确定该药物的关键时间窗口 最有效的策略。从这些研究中获得的结果有望推进我们的 了解认知/社会行为的基本生物学和人类神经生物学 广告进展。此外，这些研究具有重大的翻译价值，并将提供一个框架 为了改善AD中的认知和神经精神症状的新型热策略。