Astrocytic Aβ1‐42 uptake is determined by Aβ‐aggregation state and the presence of amyloid‐associated proteins

Intracerebral accumulation of amyloid-beta (A beta) leading to A beta plaque formation, is the main hallmark of Alzheimer's disease and might be caused by defective A beta-clearance. We previously found primary human astrocytes and microglia able to bind and ingest A beta 1-42 in vitro, which appeared to be limited by A beta 1-42 fibril formation. We now confirm that astrocytic A beta-uptake depends on size and/or composition of A beta-aggregates as astrocytes preferably take up oligomeric A beta over fibrillar A beta. Upon exposure to either fluorescence-labelled A beta 1-42 oligomers (A beta(oligo)) or fibrils (A beta(fib)), a larger (3.7 times more) proportion of astrocytes ingested oligomers compared to fibrils, as determined by flow cytometry. A beta-internalization was verified using confocal microscopy and live-cell imaging. Neither uptake of A beta(oligo) nor A beta(fib), triggered proinflammatory activation of the astrocytes, as judged by quantification of interleukin-6 and monocyte-chemoattractant protein-1 release. Amyloid-associated proteins, including alpha1-antichymotrypsin (ACT), serum amyloid P component (SAP), C1q and apolipoproteins E (ApoE) and J (ApoJ) were earlier found to influence A beta-aggregation. Here, astrocytic uptake of A beta(fib) increased when added to the cells in combination with SAP and C1q (SAP/C1q), but was unchanged in the presence of ApoE, ApoJ and ACT. Interestingly, ApoJ and ApoE dramatically reduced the number of A beta(oligo)-positive astrocytes, whereas SAP/C1q slightly reduced A beta(oligo) uptake. Thus, amyloid-associated proteins, especially ApoJ and ApoE, can alter A beta-uptake in vitro and hence may influence A beta clearance and plaque formation in vivo.