Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. The neuropathological hallmarks include extracellular senile plaques consisting of deposited beta-amyloid (Abeta) peptides and intraneuronal neurofibrillary tangles. Neuroinflammation and activation of astrocytes are also well-established features of AD neuropathology; however, the relationships between astrocytes and Abeta deposition remain unclear. Previous studies have shown that adult mouse astrocytes internalize and degrade Abeta deposits in brain sections prepared from human amyloid precursor protein (APP) transgenic mice. In the present study, we demonstrate that cultured adult, but not neonatal mouse astrocytes, respond morphologically and degrade Abeta deposits present in human AD brain. We also transplanted astrocytes isolated from enhanced green fluorescent protein expressing adult and neonatal mice into the hippocampi of human Abeta plaque-bearing transgenic APPSwe+PS1dE9 (APdE9) mice and their wild-type littermates and followed the migration and localization of these astrocytes by confocal microscopy upto 7 days after transplantation. Posttransplantation the astrocytes localized as aggregates or thin strings of many cells within the hippocampi of APdE9 and wild-type mice and showed limited migration from the injection site. Interestingly, most of the transplanted astrocytes were found near Abeta deposits in the hippocampi of APdE9 mice. In contrast to findings in ex vivo degradation assay, confocal microscopy revealed that both adult and neonatal transplanted astrocytes internalized human Abeta immunoreactive material in vivo. These results support the role of astrocytes as active Abeta clearing cells in the CNS that may have important implications for future development of therapeutic strategies for AD.
Pihlaja
Rea
R
Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, and Department of Oncology, Kuopio University Hospital, Finland.
Koistinaho
Jari
J
Malm
Tarja
T
Sikkilä
Herkko
H
Vainio
Seppo
S
Koistinaho
Milla
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology*; D002465:Cell Movement; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D049452:Green Fluorescent Proteins