Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Abstract

Recent studies suggest that bone marrow-derived macrophages can effectively reduce ␤-amyloid (A␤) deposition in brain. To further elucidate the mechanisms by which macrophages degrade A␤, we cultured murine macrophages on top of A␤ plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP 717VϾF 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 A␤ 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 A␤ degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading A␤ than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of A␤ 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 A␤-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 A␤ degradation by macrophages. These apoE isoform-dependent effects of macrophages on A␤ degradation suggest a novel "peripheral" mechanism for A␤ clearance from brain that may also, in part, explain the isoformdependent effects of apoE in determining the genetic risk for Alzheimer's disease.

Amyloid-β Increases Metallo- and Cysteine Protease Activities in Human Macrophages

“…Results from the present study show that human macrophages can avidly internalize Aβ and that this process has an effect on MMP-9 activation, in agreement with previous results in mice peritoneal macrophages [19]. However, our study shows that in human macrophages, in contrast to the results in mouse peritoneal macrophages, Aβ peptides exerted an upregulatory effect not only on MMP-9, but also on MMP-2 expression and abundance.…”

“…Most of these interactions are pathological for the cells. It has been previously reported that macrophages have the ability to internalize and degrade Aβ in an apoE-facilitated manner [19]. These authors suggested that macrophage-mediated Aβ degradation is, in part, mediated by secretion of matrix metalloproteinase-9 (MMP-9).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In transgenic mice models (see Table 6), MMP-9 expression is further triggered by neurons upon exposure to Ab derived peptides and macrophages induces MMP-9 expression to get Ab clearance (Deb et al, 2003;Guo et al, 2006;Zhao et al, 2009).…”

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

“…The apoE gene encodes a 34-kDa protein that is expressed throughout the brain. It is synthesized and secreted by astrocytes and microglia and involved in the regulation of the lipid metabolism (Boyles et al, 1985;Xu et al, 2006;Riddell et al, 2008;Zhao et al, 2009 (Urosevic and Martins, 2008). Two recent studies provided novel molecular mechanism for the impaired Aβ clearance that may explain the strong isoform-dependent effects of ApoE in determining the genetic risk for AD.…”