title: M2 Macrophage Transplantation Ameliorates Cognitive Dysfunction in Amyloid-β-Treated Rats Through Regulation of Microglial Polarization.
abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-β (Aβ) aggregation is considered to be the critical factor underlying AD pathological mechanisms. Alternatively activated (M2) macrophages/microglia have been reported to have neuroprotective effects in neurodegenerative disease. In this study, we characterized the neuroprotective effects of M2 macrophage transplantation in AD model rats and investigated the underlying mechanisms. Intracerebroventricular injection of Aβ1 - 42 to rats was used to model AD and resulted in cognitive impairment, neuronal damage, and inflammatory changes in the brain microenvironment. We observed an increased interferon regulatory factor (IRF) 5/IRF4 ratio, resulting in greater production of classically activated (M1) versus M2 microglia. M2 macrophage transplantation attenuated inflammation in the brain, reversed Aβ1 - 42-induced changes in the IRF4-IRF5 ratio, drove endogenous microglial polarization toward the M2 phenotype, and ameliorated cognitive impairment. Nerve growth factor (NGF) treatment reduced the IRF5/IRF4 ratio and induced primary microglial polarization to the M2 phenotype in vitro; these effects were prevented by tyrosine Kinase Receptor A (TrkA) inhibition. M2 macrophage transplantation restored the balance of IRF4-IRF5 by affecting the expression of NGF and inflammatory cytokines in the brains of AD model rats. This drove microglial polarization to the M2 phenotype, promoted termination of neuroinflammation, and resulted in improved cognitive abilities.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Yan-Yong
authors.initials: YY
authors.lastname: Liu
authors.forename: Ji
authors.initials: J
authors.lastname: Zheng
authors.forename: Chao
authors.initials: C
authors.lastname: Ji
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Zuo
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000276:immunology / Q000473:pathology / Q000628:therapy; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D011897:Random Allocation; D011916:Rats, Inbred F344; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D016229:Amyloid beta-Peptides; D050835:Interferon Regulatory Factors; D020932:Nerve Growth Factor; D010446:Peptide Fragments; D020917:Receptor, trkA; D000099218:Interferon Regulatory Factor-4; C000613821:IRF5 protein, rat; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; M2 macrophage; microglial polarization; nerve growth factor; neuroinflammation