期刊
JOURNAL OF NEUROCHEMISTRY
卷 111, 期 6, 页码 1409-1424出版社
WILEY
DOI: 10.1111/j.1471-4159.2009.06402.x
关键词
anti-inflammatory; glial scar; matrix metalloproteinases; monocytes; neurodegeneration; vaccination
资金
- Marciano Family Foundation
- US Navy Bureau of Medicine and Surgery
Immunization with an altered myelin-derived peptide (MOG45D) improves recovery from acute CNS insults, partially via recruitment of monocyte-derived macrophages that locally display a regulatory activity. Here, we investigated the local alterations in the cellular and molecular immunological milieu associated with attenuation of Alzheimer's disease-like pathology following immunotherapy. We found that immunization of amyloid precursor protein/presenilin 1 double-transgenic mice with MOG45D peptide, loaded on dendritic cells, led to a substantial reduction of parenchymal and perivascular amyloid beta (A beta)-plaque burden and soluble A beta((1-42)) peptide levels as well as reduced astrogliosis and levels of a key glial scar protein (chondroitin sulphate proteoglycan). These changes were associated with a shift in the local innate immune response, manifested by increased Iba1+/CD45high macrophages that engulfed A beta, reduced pro-inflammatory (tumor necrosis factor-alpha) and increased anti-inflammatory (interleukin-10) cytokines, as well as a significant increase in growth factors (IGF-1 and TGF beta) in the brain. Furthermore, the levels of matrix metalloproteinase-9, an enzyme shown to degrade A beta and is associated with glial scar formation, were significantly elevated in the brain following immunization. Altogether, these results indicate that boosting systemic immune cells leads to a local immunomodulation manifested by elevated levels of anti-inflammatory cytokines and metalloproteinases that contribute to ameliorating Alzheimer's disease pathology.
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