Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9.
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 (Abeta)-plaque burden and soluble Abeta((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+/CD45(high) macrophages that engulfed Abeta, 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 TGFbeta) in the brain. Furthermore, the levels of matrix metalloproteinase-9, an enzyme shown to degrade Abeta 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.
Department of Neurosurgery, the Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angels, California 90048, USA. Maya.koronyo@cshs.org
Maya
M
Koronyo-Hamaoui
Minhee K
MK
Ko
Yosef
Y
Koronyo
David
D
Azoulay
Akop
A
Seksenyan
Gilad
G
Kunis
Michael
M
Pham
Joshua
J
Bakhsheshian
Patricia
P
Rogeri
Keith L
KL
Black
Daniel L
DL
Farkas
Michal
M
Schwartz
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000276:immunology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006023:Glycoproteins / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000378:metabolism / Q000627:therapeutic use; D053764:Presenilin-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011508:Chondroitin Sulfate Proteoglycans; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D016212:Transforming Growth Factor beta; C075222:amyloid beta-protein (1-42); C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; D007334:Insulin-Like Growth Factor I; D020780:Matrix Metalloproteinase 9