Macrophage-mediated degradation of beta-amyloid via an apolipoprotein E isoform-dependent mechanism.

TitleMacrophage-mediated degradation of beta-amyloid via an apolipoprotein E isoform-dependent mechanism.
Publication TypeJournal Article
Year of Publication2009
AuthorsZhao L, Lin S, Bales KR, Gelfanova V, Koger D, DeLong C, Hale J, Liu F, Hunter JM, Paul SM
JournalJ Neurosci
Date Published2009 Mar 18
KeywordsAlzheimer Disease, Amyloid, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Apolipoproteins E, Cells, Cultured, Coculture Techniques, Humans, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Isoforms

Recent studies suggest that bone marrow-derived macrophages can effectively reduce beta-amyloid (Abeta) deposition in brain. To further elucidate the mechanisms by which macrophages degrade Abeta, we cultured murine macrophages on top of Abeta plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP(717V>F) mutation driven by the platelet-derived growth factor promoter]. Using this ex vivo assay, we found that macrophages from wild-type mice very efficiently degrade both soluble and insoluble Abeta in a time-dependent manner and markedly eliminate thioflavine-S positive amyloid deposits. Because macrophages express and secrete apolipoprotein E (apoE), we compared the efficiency of Abeta degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading Abeta than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of Abeta was effectively blocked by an anti-apoE antibody and receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, suggesting involvement of LDL receptors. Measurement of matrix metalloproteinase-9 (MMP-9) activity in the media from human apoE-expressing macrophages cocultured with Abeta-containing brain sections revealed greater levels of MMP-9 activity in apoE2-expressing than in either apoE3- or apoE4-expressing macrophages. Differences in MMP-9 activity appear to contribute to the isoform-specific differences in Abeta degradation by macrophages. These apoE isoform-dependent effects of macrophages on Abeta degradation suggest a novel "peripheral" mechanism for Abeta clearance from brain that may also, in part, explain the isoform-dependent effects of apoE in determining the genetic risk for Alzheimer's disease.

Alternate JournalJ. Neurosci.
PubMed ID19295164