Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 52, Issue 2, Pages 483-495Publisher
IOS PRESS
DOI: 10.3233/JAD-151090
Keywords
Alzheimer's disease; M2 macrophage; microglial polarization; nerve growth factor; neuroinflammation
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Funding
- National Natural Science Foundation of China [81100801]
- Scientific Research Foundation of Graduate School of Peking Union Medical College
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Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-beta (A beta) 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 A beta(1-42) 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 A beta(1-42)-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.
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