Serotonergic IL-1R1 and Neuropsychiatric Traits of an Alzheimer's Mouse Model

血清素能 IL-1R1 和阿尔茨海默病小鼠模型的神经精神特征

• 批准号: 10452857
• 负责人: Uri Ashery
• 金额: $ 37.92万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452857
• 关键词: Address; Affective; Age; Agitation; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Animal Disease Models; Anti-Inflammatory Agents; Antidepressive Agents; Anxiety; Astrocytes; Attention; Automobile Driving; Behavior; Behavior assessment; Behavioral; Behavioral Genetics; Biochemical; Cells; Characteristics; Chronic; Cognition; Cognitive; Cognitive deficits; Cytokine Receptors; Cytopathology; Data; Dementia; Dependence; Disease; Drug usage; Ectopic Expression; Emotional; Etiology; Evaluation; Female; Foundations; Functional disorder; Funding; Gene Mutation; Genetic Diseases; Hippocampus (Brain); Human; Immune; Immune system; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune System; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Lead; Major Depressive Disorder; Mediating; Memory; Memory Loss; Mental Depression; Messenger RNA; Microglia; Monitor; Mood Disorders; Moods; Mus; Mutation; Neurodegenerative Disorders; Neurons; Pathology; Persons; Physiological; Physiology; Play; Production; Prosencephalon; Proteins; Receptor Activation; Receptor Signaling; Reporting; Rewards; Role; Selective Serotonin Reuptake Inhibitor; Senile Plaques; Serotonin; Serotonin Antagonists; Signal Transduction; Site; Specificity; Synaptic plasticity; Testing; Visuospatial; Work; affective disturbance; antagonist; cognitive function; common symptom; comorbidity; cytokine; depressive symptoms; extracellular; in vivo; information processing; inhibitor therapy; male; mouse model; negative affect; neural circuit; neurogenesis; neuroinflammation; neuropsychiatric symptom; neuropsychiatry; novel therapeutics; raphe nuclei; receptor expression; reuptake; sex; social engagement; trait

Project Summary In addition to its well-known cognitive deficits, Alzheimer’s disease (AD) is often associated with debilitating changes in affective behavior, including anxiety, depression and altered social engagement. Mechanistic connections between the hallmark cytopathologies of AD and neuropsychiatric traits remains poorly defined. Both AD and mood disorders have been associated with neuroinflammation, with CNS elevations of the major pro-inflammatory mediator IL-1β seen in both disorders. We and others have found that serotonin (5-HT) synthesizing neurons are relatively unique as neuronal sites of expression of the receptor for IL-1β, IL-1R1. Serotonergic projections to the hippocampus, a site of significant, inflammatory cytokine-inducing pathology in AD, are believed to contribute to both cognition and mood. We have shown that serotonergic IL-1R1 activation leads to rapid elevations in activity of the antidepressant-sensitive 5-HT transporter (SERT), enhancing clearance of 5-HT and diminishing extracellular 5-HT availability. Others have shown that while AD pathology extends to forebrain-projecting serotonergic raphe nuclei it also leads to and ectopic expression of SERT by astrocytes. These combined effects can diminish the capacity for serotonergic signaling, reduced anti- inflammatory 5-HT stimulation of microglia, further increasing IL-1 levels and promoting negative affective states. In this regard, recent studies have indicated that SERT antagonism by 5-HT-selective reuptake inhibitors (SSRIs), drugs used to treat affective disorders in AD patients, has been reported to reduce A plaque burden as well as cognitive deficits in AD. We propose that IL-1β elevations that arise as a consequence of AD pathology lead to alterations in 5-HT signaling in the hippocampus via serotonergic IL-1R1 activation, changes that can accelerate cytopathologies, disrupt the function and plasticity of 5-HT modulated hippocampal circuitry, and support both affective and cognitive disturbances observed in AD. Here we pursue our hypothesis through a unique, four-way collaborative project involving an expert in SERT and serotonergic dysfunction (Blakely), an expert in the evaluation of hippocampal physiology and the study of AD genetic mouse models (Ashery), an expert in the signaling and functional contributions of IL-1R1s (Quan), and an expert in assessment of the behavior of genetic mouse models (Hahn). We utilize a conditional strategy to eliminate IL-1 signaling specifically in serotonergic raphe neurons in an AD mouse model (5XFAD), attentive to issues of sex- dependence. Through our efforts, we will determine whether the biochemical, cellular, physiological and affective/cognitive disturbances that arise from 5XFAD mutations require IL-1R1 signaling to 5-HT neurons. Data obtained in this effort can then be extended through more sustained funding to further elucidate the timing, mechanisms and broader circuit specificities driving, and responding to, these changes.

项目概要 除了众所周知的认知缺陷之外，阿尔茨海默病 (AD) 还常常与衰弱有关。 情感行为的变化，包括焦虑、抑郁和社交参与。 AD 的标志性细胞病理学与神经精神特征之间的联系仍然不明确。 AD 和情绪障碍都与神经炎症有关，其中主要的中枢神经系统升高 我们和其他人发现血清素 (5-HT) 存在于这两种疾病中。 合成神经元作为 IL-1β、IL-1R1 受体表达的神经元位点相对独特。 海马体的血清素能投射，海马体是重要的炎症细胞因子诱导病理的部位 AD 被认为有助于认知和情绪 我们已经证明血清素能 IL-1R1 激活。 导致抗抑郁药敏感的 5-HT 转运蛋白 (SERT) 活性快速升高，增强 5-HT 的清除和细胞外 5-HT 可用性的减少其他人已经表明，而 AD 病理学。 延伸至前脑投射的血清素能中缝核，它还导致 SERT 的异位表达 这些综合作用可以降低血清素信号的能力，减少抗- 炎症性 5-HT 刺激小胶质细胞，进一步增加 IL-1 水平并促进负面情绪 在这方面，最近的研究表明 5-HT 选择性再摄取抑制剂具有 SERT 拮抗作用。 据报道，用于治疗 AD 患者情感障碍的药物（SSRIs）可减少 A 斑块负担 以及 AD 中的认知缺陷，我们认为 IL-1β 升高是 AD 病理学的结果。 通过血清素能 IL-1R1 激活导致海马 5-HT 信号传导发生改变，这些改变可以 加速细胞病理学，破坏 5-HT 调节的海马回路的功能和可塑性，以及 支持 AD 中观察到的情感和认知障碍。在这里，我们通过 独特的四方合作项目，涉及 SERT 和血清素能功能障碍方面的专家 (Blakely) 海马生理学评估和AD遗传小鼠模型研究专家（Ashery） IL-1R1 信号传导和功能贡献方面的专家 (Quan)，以及 IL-1R1 的评估专家 我们利用条件策略来消除 IL-1 信号传导。 特别是在AD小鼠模型（5XFAD）的血清素中缝神经元中，关注性问题 通过我们的努力，我们将确定是否存在生化、细胞、生理和依赖性。 5XFAD 突变引起的情感/认知障碍需要向 5-HT 神经元发送 IL-1R1 信号。 然后可以通过更持续的资金来扩展在这一努力中获得的成果，以进一步阐明时间安排， 驱动和响应这些变化的机制和更广泛的电路特性。

项目成果

Super-Resolution-Chip: an in-vitro platform that enables super-resolution microscopy of co-cultures and 3D systems.

超分辨率芯片：一种体外平台，可实现共培养和 3D 系统的超分辨率显微镜检查。

• 发表时间: 2023-10-01
• 影响因子: 3.4
• 作者: Sade, Ofir;Boneberg, Ronja;Weiss, Yifat;Beldjilali;Leichtmann;Talpir, Itay;Gottfried, Irit;Ashery, Uri;Rauti, Rossana;Maoz, Ben M
• 通讯作者: Maoz, Ben M

Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.

装载单克隆抗体的脑靶向脂质体可减少α-突触核蛋白聚集并改善帕金森病的行为症状。

• 发表时间: 2023-12
• 作者: Sela, Mor;Poley, Maria;Mora;Kagan, Shaked;Avital, Aviram;Kaduri, Maya;Chen, Gal;Adir, Omer;Rozencweig, Adi;Weiss, Yfat;Sade, Ofir;Leichtmann;Simchi, Lilach;Aga;Bell, Batia;Yeretz
• 通讯作者: Yeretz