How to modulate innate immune function to prevent age-related neurodegeneration

如何调节先天免疫功能以预防与年龄相关的神经退行性疾病

• 批准号: 9280836
• 负责人: GREGORY M COLE
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280836
• 关键词: Acute; Adaptor Signaling Protein; Adult; Adverse effects; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloidosis; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Attenuated; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Cells; Brain; Cells; Chronic; Clinical Trials; Cognitive; Complex; Curcumin; Data; Dementia; Dependence; Diet; Dose; Enrollment; Equilibrium; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Models; Genotype; Goals; Human; Ibuprofen; Immune; Immune System Diseases; Immune System and Related Disorders; Immunologic Markers; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1; Intervention; Knockout Mice; Knowledge; Mediating; Microglia; Modeling; Molecular Target; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Plasmids; Play; Population; Presenile Alzheimer Dementia; Prevention trial; Production; Protein Isoforms; Regimen; Regulation; Risk; Risk Factors; Rodent; Role; Severity of illness; Signal Transduction; Surface; Synapses; System; TREM2 gene; TYROBP gene; Tauopathies; Testing; Tg2576; Therapeutic; Tissue Banks; Tissues; Toxic effect; Toxin; Transgenic Mice; Transgenic Model; Translations; Traumatic Brain Injury; Veterans; Viral Vector; age related; age related neurodegeneration; apolipoprotein E-4; base; brain tissue; cyclooxygenase 2; design; experimental study; genetic association; hTau Mice; immunoregulation; in vivo; indexing; inflammatory milieu; innate immune function; innovation; mitogen-activated protein kinase p38; neuroinflammation; neuroprotection; neurotoxic; novel strategies; outcome prediction; overexpression; predicting response; prevent; public health relevance; receptor; repaired; repository; response; small molecule; tau Proteins; tau-protein kinase

DESCRIPTION (provided by applicant): Age-related neurodegenerative diseases (including AD, PD and FTD), obesity and traumatic brain injury all exhibit imbalanced innate immune responses. This contributes to chronic neuroinflammation, which is driven by unresolved microglial activation, leading to toxin release and failed repair mechanisms. Recent genetic-association discoveries imply an important role for two innate immune genes, TREM2 (for AD, PD, FTD) and CD33 (AD), suggesting chronic neuroinflammation may be a causative factor in these conditions. Both the AD TREM2 mutation or loss of TREM2 or its signal transduction partner, TyroBP (DAP12), cause aberrant neuroinflammation. Furthermore, integrated bioinformatics identify TyroBP as the major signaling hub associated with altered gene expression in AD. Decreasing CD33 (which opposes TREM2/TyroBP signaling) reduces AD risk, while increasing TREM2/TyroBP signaling suppresses neurotoxic inflammation and promotes phagocytosis. We hypothesize that restoring effective TREM2/CD33 signaling around the TyroBP hub will suppress the amyloidosis and inflammation-driven tauopathy seen in dementia. Our group screened conventional and alternative NSAIDs in AD models and identified an intervention, curcumin, that lowers CD33 but raises TREM2 and TyroBP to restore the TREM2/CD33 balance. This is the first evidence of a small molecule that favorably targets either of these new AD genes. These data are consistent with the reductions in amyloid seen with the microglial phagocytic phenotype found in Avaccinated subjects. Design: We propose to evaluate these hypotheses using NSAID interventions in vivo studies with human E3FAD or E4FAD and human tau (htau) transgenic mice and with rodent and adult human microglia. In addition we will take advantage of our large repository of tissue from our prior studies of different NSAID regimens and transgenic models, which resulted in increased or decreased pathogenesis. We also examine associations of blood biomarkers of innate immune phenotypes with brain or cognitive responsiveness in these animal studies in our current trial of curcumin in Veterans with MCI. Objectives: To identify immunomodulatory targets that modulate microglial activation to suppress toxicity yet retain or enhance beneficial functions, and to determine how the pre-existing inflammatory milieu impacts NSAID responsiveness. Aim 1 examines how modulation of TREM2/CD33/TyroBP determines biphasic responses to NSAID on amyloid or human tau burden in vivo and if selective manipulation of human CD33 levels opposes TREM2/TyroBP signaling in cultured microglia. Aim 2 examines dose-dependent short term effects of ibuprofen and curcumin on TREM2/CD33 in E3FAD mice and the impact of specifically blocking TREM2 signaling on pathogenesis and curcumin efficacy. Aim 3 explores the involvement of NF?B-regulation of the TREM2 pathway in ApoE isoform-dependent responses to chronic NSAIDs. Since obesity increases neuroinflammation found in aging and tauopathy, Aim 4 will test NSAID modulation of and role of TREM2/CD33 balance in aging obese htau Tg mice using a TREM2 decoy. Finally, in Aim 5, we examine the responsiveness of the TREM2/CD33 pathway in adult human microglia to Aand/or NSAIDs (and differences with rodent microglia, Aim 1B) and in PBMC cells from patients in our curcumin clinical trial. Feasibility: Our strong preliminary data, added collaborators, and our large bank of NSAID treated AD animal model brain tissue suggest high feasibility. Potential Outcomes. Completion of these aims should fill human vs. rodent knowledge gaps and establish the roles of TREM2/TyroBP as potential molecular target(s) of innate immune dysfunction that can be modulated by select NSAIDs at doses that limit either NF?B or COX targets. Selectively modulating TREM2 and CD33 in genetic models of the major AD risk factors and pathologies will be used to determine the relevance of TREM2/CD33/TyroBP pathways to pathogenesis. These studies will facilitate an innovative and urgently needed new approach to AD prevention.

描述（由申请人提供）：