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.

项目总结

项目成果

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

• DOI: 10.1002/adma.202304654
• 发表时间: 2023-12
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Sela M;Poley M;Mora-Raimundo P;Kagan S;Avital A;Kaduri M;Chen G;Adir O;Rozencweig A;Weiss Y;Sade O;Leichtmann-Bardoogo Y;Simchi L;Aga-Mizrachi S;Bell B;Yeretz-Peretz Y;Or AZ;Choudhary A;Rosh I;Cordeiro D;Cohen-Adiv S;Berdichevsky Y;Odeh A;Shklover J;Shainsky-Roitman J;Schroeder JE;Hershkovitz D;Hasson P;Ashkenazi A;Stern S;Laviv T;Ben-Zvi A;Avital A;Ashery U;Maoz BM;Schroeder A
• 通讯作者: Schroeder A