title: Multiple cellular and molecular mechanisms are involved in human Aβ clearance by transplanted adult astrocytes.
abstract: Astrocytes and microglia are able to degrade potentially neurotoxic β-amyloid (Aβ) deposits typical for Alzheimer's disease (AD) pathology. Contrary to microglia, astrocytes degrade human Aβ from tissue sections in vitro without any additional stimulation, but it has remained unclear whether transplanted astrocytes are able to clear deposited human Aβ in vivo. We transplanted adult mouse astrocytes into the hippocampi of transgenic mice mimicking AD and observed their fate, effects on microglial responses, and Aβ clearance. After 2-months follow-up time, we discovered a significant reduction in Aβ burden compared with AD mice infused with PBS only. The remaining Aβ deposits were fragmented and most of the Aβ immunoreactivity was seen within the transplanted astrocytes. Concomitant to Aβ reduction, both CD68 and CD45 immunoreactivities were significantly upregulated but phagocytic microglia were often surrounding and engulfing Aβ burdened, TUNEL-positive astrocytes rather than co-localizing with Aβ alone. Astrocytes are known to degrade Aβ also by secreting proteases involved in Aβ catabolism. To study the contribution of neprilysin (NEP), angiotensin-converting enzyme-1 (ACE-1), and endothelin-converting enzyme-2 (ECE-2) in human Aβ clearance, we utilized an ex vivo assay to demonstrate that adult astrocytes respond to human Aβ 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 Aβ from the tissue suggesting an important role for these proteases in Aβ clearance by adult astrocytes ex vivo.
authors.affiliation: Department of Neurobiology, A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Rea
authors.initials: R
authors.lastname: Pihlaja
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.forename: Riitta
authors.initials: R
authors.lastname: Kauppinen
authors.forename: Jouko
authors.initials: J
authors.lastname: Sandholm
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Milla
authors.initials: M
authors.lastname: Koistinaho
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000637:transplantation*; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016282:Aspartic Acid Endopeptidases; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D000072396:Endothelin-Converting Enzymes; D017493:Leukocyte Common Antigens; D008666:Metalloendopeptidases; D008840:Microfilament Proteins; D015260:Neprilysin; D007703:Peptidyl-Dipeptidase A; D011480:Protease Inhibitors; C112986:AIF1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C488034:ACE protein, human; C000606924:ECE2 protein, human; C000606926:Ece2 protein, mouse