Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro

Defective clearance of the amyloid-beta peptide (A beta) from the brain is considered a strong promoter in Alzheimer's disease (AD) pathogenesis. Astrocytes and microglia are important mediators of A beta clearance and A beta aggregation state and the presence of amyloid associated proteins (AAPs), such as Apolipoproteins E and J (ApoE and ApoJ), may influence A beta clearance by these cells. Here we set out to investigate whether astrocytes and microglia differ in uptake efficiency of A beta oligomers (A beta(oligo)) and A beta fibrils (A beta(fib)), and whether the A beta aggregation state and/or presence of AAPs affect A beta uptake in these cells in vitro. Adult human primary microglia and astrocytes, isolated from short delay post-mortem brain tissue, were exposed to either A beta(oligo) or A beta(fib) alone or combined with a panel of certain AAPs whereafter A beta-positive cells were quantified using flow cytometry. Upon exposure to A beta combined with ApoE, ApoJ, alpha 1-antichymotrypsin (ACT) and a combination of serum amyloid P and complement C1q (SAP-C1q), a clear reduction in astrocytic but not microglial A beta(oligo) uptake, was observed. In contrast, A beta(fib) uptake was strongly reduced in the presence of AAPs in microglia, but not in astrocytes. These data provide the first evidence of distinct roles of microglia and astrocytes in A beta clearance. More importantly we show that A beta clearance by glial cells is negatively affected by AAPs like ApoE and ApoJ. Thus, targeting the association of A beta with AAPs, such as ApoE and ApoJ, could serve as a therapeutic strategy to increase A beta clearance by glial cells. GLIA 2014;62:493-503