Unraveling the β-amyloid clearance by astrocytes: Involvement of metabotropic glutamate receptor 3, sAPPα, and class-A scavenger receptor

The mechanics of beta-amyloid (A beta) clearance by astrocytes has not been univocally described, with different mediators appearing to contribute to this process under different conditions. Our laboratory has demonstrated neuroprotective effects of astroglial subtype 3 metabotropic glutamate receptor (mGlu3R), which are dependent on the secreted form of the amyloid precursor protein (sAPP alpha) as well as on A beta clearance; however, the mechanism underlying mGlu3R-induced A beta uptake by astrocytes remains unclear. The present study shows that conditioned medium from mGlu3R-stimulated astrocytes increased A beta uptake by naive astrocytes through a mechanism dependent on sAPP alpha, since sAPP alpha depletion from conditioned medium inhibited A beta phagocytosis. Concordantly, recombinant sAPP alpha also increased A beta uptake. Since we show that both sAPP alpha and the mGlu3R agonist LY379268 increased expression of class-A scavenger receptor (SR-A) in astrocytes, we next determined whether SR-A mediates mGlu3R- or sAPP alpha-induced A beta uptake by using astrocyte cultures derived from SR-A knockout mice. We found that the effects of LY379268 as well as sAPP alpha on A beta uptake were abolished in SR-Adeficient astrocytes, indicating a major role for this scavenger receptor in LY379268- and sAPP alpha-stimulated A beta clearance by astrocytes. We also show results of coimmunoprecipitation and functional assays offering evidence of possible heterotrimerization of sAPP alpha with A beta and SR-A which could allow A beta to enter the astrocyte. In conclusion the present paper describes a novel pathway for A beta clearance by astrocytes involving sAPP alpha as an enhancer of SR-A-dependent A beta phagocytosis.