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

The Alzheimer Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Glia (Impact Factor: 6.03). 08/2010; 58(10):1235 - 1246. DOI: 10.1002/glia.21004
Source: PubMed


Intracerebral accumulation of amyloid-β (Aβ) leading to Aβ plaque formation, is the main hallmark of Alzheimer's disease and might be caused by defective Aβ-clearance. We previously found primary human astrocytes and microglia able to bind and ingest Aβ1-42 in vitro, which appeared to be limited by Aβ1-42 fibril formation. We now confirm that astrocytic Aβ-uptake depends on size and/or composition of Aβ-aggregates as astrocytes preferably take up oligomeric Aβ over fibrillar Aβ. Upon exposure to either fluorescence-labelled Aβ1-42 oligomers (Aβoligo) or fibrils (Aβfib), a larger (3.7 times more) proportion of astrocytes ingested oligomers compared to fibrils, as determined by flow cytometry. Aβ-internalization was verified using confocal microscopy and live-cell imaging. Neither uptake of Aβoligo nor Aβfib, triggered proinflammatory activation of the astrocytes, as judged by quantification of interleukin-6 and monocyte-chemoattractant protein-1 release. Amyloid-associated proteins, including α1-antichymotrypsin (ACT), serum amyloid P component (SAP), C1q and apolipoproteins E (ApoE) and J (ApoJ) were earlier found to influence Aβ-aggregation. Here, astrocytic uptake of Aβfib 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 Aβoligo-positive astrocytes, whereas SAP/C1q slightly reduced Aβoligo uptake. Thus, amyloid-associated proteins, especially ApoJ and ApoE, can alter Aβ-uptake in vitro and hence may influence Aβ clearance and plaque formation in vivo. © 2010 Wiley-Liss, Inc.

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Available from: Henrietta M Nielsen
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