Role of CXCR2 in beta-amyloid Induced Neurodegeneration

CXCR2 在 β-淀粉样蛋白诱导的神经变性中的作用

• 批准号: 8146199
• 负责人: GUO-HUANG FAN
• 金额: $ 37.66万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8146199
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Astrocytes; Behavior assessment; Brain; Brain region; Cessation of life; Clinical; Excitatory Amino Acids; Exhibits; Failure; Glutamates; Hippocampus (Brain); Human; IL8RB gene; Impairment; In Vitro; Inflammatory; Infusion procedures; Interleukin-8B Receptor; Interruption; Irritants; Knockout Mice; Ligands; MEKs; Mediating; Microglia; Mus; Mutant Strains Mice; N-Methylaspartate; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neuronal Injury; Neurons; Pathogenesis; Pathway interactions; Patients; Peptides; Phosphorylation; Prevention; Recycling; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenic Mice; Wild Type Mouse; attenuation; base; chemokine; chemokine receptor; cytokine; desensitization; extracellular; in vivo; mutant; neuron loss; neuroprotection; neurotoxic; neurotoxicity; overexpression; receptor; receptor sensitivity; research study; response; tool

Chemokines are up-regulated in the brain of Alzheimer's disease patients and are produced after amyloid-beta stimulation of glial cells.Based on these initial findings, we propose the following hypothesis: 1) some (if not all) chemokines produced by the reactive glial cells protect neurons against the toxicity of amyloid-b peptide through activation of the cognate chemokine receptors. 2) Specific signaling pathways initiated by the chemokine receptors are involved in the chemokine receptor-mediated neuroprotection. 3) Chemokine receptors in the inflamed CNS become constitutively desensitized due to the over-stimulation of the receptors by the excessive chemokines and excitatory amino acids produced by the activated astrocytes and microglial cells, thus resulting in attenuation of the chemokine receptor-mediated neuroprotection in clinical settings, such as those occuring in Alzheimer's disease. I propose the following specific aims to test these hypotheses. Aim 1. To determine whether CXCR2 is involved in the protection against amyloid-b peptide-induced neuronal death using CXCR2 knock-out mice and a selective CXCR2 antagonist in transgenic mice overexpressing human mutant human amyloid precursor protein as experimental tools. Aim 2. To determine the signaling pathways of CXCR2 involved in the receptor-mediated neuroprotection against amyloid-b peptide -induced neuronal damage. . To examine the contribution of glutamate- and chemokine-induced receptor desensitization and impairment of receptor resensitization to the failure of CXCR2 overexpression in AD to protect against neurodegeneration: Several important fundamental understandings will result from our studies, all of which have signficance for the understanding of the pathogenesis of neurodegenerative disease and its therapeutic interruption or prevention. First, we will clarify the role of the CXCR2 receptor in neuroprotection from pathways activated by b-Amyloid protein, in vitro and in vivo, utilizing complementary morphological, functional and behavioral assessments. Second, we will test the hypothesis that chemokinemediated signaling relevant for neuroprotection is counteracted by NMDA via mechanisms related to interruption of CXCR2 recycling and regeneration of receptor sensitivity to endogenous chemokines produced in excess in pathological settings, providing evidence for useful strategies for therapeutic intervention in AD and other neurodegenerative diseases.

趋化因子在阿尔茨海默病患者的大脑中上调，并在淀粉样蛋白- β后产生