Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9

J Neurochem. 2009 Dec;111(6):1409-24. doi: 10.1111/j.1471-4159.2009.06402.x. Epub 2009 Sep 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease* / immunology
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / immunology
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Glycoproteins / therapeutic use
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-10 / metabolism*
  • Male
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments / metabolism
  • Peptide Fragments / therapeutic use
  • Presenilin-1 / genetics
  • Transforming Growth Factor beta / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Chondroitin Sulfate Proteoglycans
  • Glycoproteins
  • Myelin-Oligodendrocyte Glycoprotein
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Transforming Growth Factor beta
  • amyloid beta-protein (1-42)
  • myelin oligodendrocyte glycoprotein (35-55)
  • Interleukin-10
  • Insulin-Like Growth Factor I
  • Matrix Metalloproteinase 9