Multiple Cellular and Molecular Mechanisms Are Involved in Human Aβ Clearance by Transplanted Adult Astrocytes

Astrocytes and microglia are able to degrade potentially neurotoxic beta-amyloid (A beta) deposits typical for Alzheimer's disease ( AD) pathology. Contrary to microglia, astrocytes degrade human A beta from tissue sections in vitro without any additional stimulation, but it has remained unclear whether transplanted astrocytes are able to clear deposited human A beta in vivo. We transplanted adult mouse astrocytes into the hippocampi of transgenic mice mimicking AD and observed their fate, effects on microglial responses, and A beta clearance. After 2-months follow-up time, we discovered a significant reduction in A beta burden compared with AD mice infused with PBS only. The remaining A beta deposits were fragmented and most of the A beta immunoreactivity was seen within the transplanted astrocytes. Concomitant to A beta reduction, both CD68 and CD45 immunoreactivities were significantly up-regulated but phagocytic microglia were often surrounding and engulfing A beta burdened, TUNEL-positive astrocytes rather than co-localizing with A beta alone. Astrocytes are known to degrade A beta also by secreting proteases involved in A beta catabolism. To study the contribution of neprilysin (NEP), angiotensin-converting enzyme-1 (ACE-1), and endothelin-converting enzyme-2 (ECE-2) in human A beta clearance, we utilized an ex vivo assay to demonstrate that adult astrocytes respond to human A beta by upregulating NEP expression. Further, incubation of adult astrocytes with known inhibitors of NEP, ACE-1, or ECE-2 significantly inhibited the removal of human A beta from the tissue suggesting an important role for these proteases in A beta clearance by adult astrocytes ex vivo. (C) 2011 Wiley-Liss, Inc.