Defining the Mechanistic Link between C5aR1 signaling and cognitive loss in Alzheimer's diseases

定义阿尔茨海默病中 C5aR1 信号传导与认知丧失之间的机制联系

• 批准号: 10213622
• 负责人: Seyed Ali Mortazavi
• 金额: $ 66.23万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213622
• 关键词: Ablation; Adult; Adverse effects; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Arctic Regions; Astrocytes; Behavior; Biochemical; Biochemistry; Brain; C5a anaphylatoxin receptor; Cells; Chronic; Clinical; Clinical Trials; Cognition; Cognitive deficits; Complement; Complement 5a; Complement Activation; Complement Receptor; Consensus; Cytolysis; Data; Development; Differentiation Antigens; Disease; Disease Progression; Elderly; Enterobacteria phage P1 Cre recombinase; Enzymes; Gene Deletion; Gene Expression; Genetic; Glial Fibrillary Acidic Protein; Goals; Golgi Apparatus; Hippocampus (Brain); Human; Immune system; Immunohistochemistry; Impaired cognition; Incidence; Individual; Infection; Inflammation; Inflammatory; Innate Immune System; Knockout Mice; Knowledge; Late Onset Alzheimer Disease; Lead; Ligands; Link; LoxP-flanked allele; Mediating; Memory impairment; Microglia; Microscopy; Molecular; Mus; Myelogenous; Neurites; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Receptor Inhibition; Reporting; Resolution; Role; Senile Plaques; Signal Transduction; Stains; Synapses; System; Tamoxifen; Techniques; Testing; Therapeutic; Transgenic Mice; Validation; activation product; amyloid pathology; arm; care costs; cognitive development; cognitive function; complement pathway; cost; density; differential expression; hyperphosphorylated tau; impaired capacity; inhibitor/antagonist; innate immune mechanisms; mouse model; nervous system disorder; neuron loss; novel; overexpression; pathogen; preservation; prevent; promoter; receptor; response; small molecule; spatial memory; synaptic pruning; targeted treatment; therapeutic candidate; transcriptome sequencing

Project Summary: By 2050 it is estimated that there will be 13.8 million individuals in the US with Alzheimer's disease (AD), at a cost of over $1.2 trillion per yr, if no disease-modifying therapy is developed. The relative contributions of the AD defining pathological markers, amyloid and hyperphosphorylated tau, to cognitive dysfunction remains controversial, but studies in both AD patients and transgenic mouse models of AD, have shown that amyloid is necessary but not sufficient for the development of cognitive loss which is the key clinical target of AD. There is a growing consensus that it is the response of glial cells in the brain to amyloid that is relevant to neuronal damage and thus cognitive impairment, and that the capacity to phagocytose and clear amyloid and perhaps other deleterious material in the brain may have a substantial influence on the initiation and progression of the disease. The complement cascade, a powerful effector mechanism of the immune system that is directly activated by fibrillar Aβ (fAβ), can both enhance clearance and induce inflammation. In addition, complement activation dependent excessive synapse pruning occurs in models of AD and other neurological disorders. Our data demonstrate that pharmacologic inhibition or genetic deletion of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppresses neurite and cognitive loss in mouse models of Alzheimer's disease/amyloidosis. The effects of blocking this C5a receptor interaction on astrocyte activation, inflammatory and clearance related gene expression, neuronal integrity and synaptic density are proposed in two aims here with the ultimate goal of determining mechanistic steps between activation of C5aR1 and loss of neuronal function, as well as the potential for C5aR1 antagonists as therapeutic candidates for clinical trials in humans to prevent cognitive impairment. In a third aim, we proposed to use a newly generated mouse with a floxed C5aR1, to temporally and cell specifically ablate the receptor and assess gene expression, neuronal integrity and function in an AD mouse model, to more closely mimic the adult inhibition of this receptor that would occur with receptor antagonist treatment of individuals with or at risk for AD. Selective modulation of complement activation products or their receptors may be an optimal strategy for retaining the neuroprotective and phagocytic functions of complement components, as well as systemic protection from pathogens lysis, while dampening induced inflammatory damage. Importantly, blockage of this ligand-receptor system has not shown adverse effects in humans, suggesting that C5aR1-targeted therapeutics for AD may be safely administered.

项目总结:

项目成果

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics.

• DOI: 10.1124/pharmrev.120.000072
• 发表时间: 2021-04
• 期刊: Pharmacological reviews
• 影响因子: 21.1
• 作者: Garred P;Tenner AJ;Mollnes TE
• 通讯作者: Mollnes TE