title: Retinal macroglia changes in a triple transgenic mouse model of Alzheimer's disease.
abstract: The retinas of Alzheimer's disease (AD) patients and transgenic AD animal models display amyloid beta deposits and degeneration of ganglion cells. Little is known, however, about the glial changes in the AD retina. The present study used a triple transgenic mouse model (3xTG-AD), which carries mutated human amyloid precursor protein, tau, and presenilin 1 genes and closely mimics the human brain pathology, to investigate retinal glial changes in AD. AD cognitive symptoms are known to begin in the 3xTG-AD mice at four months of age but plaques and tangles are not seen until six to twelve months. Müller cells in 3xTG-AD animals were GFAP-positive, indicating activation, at the earliest time point investigated, nine months. Astrocyte activation was also suggested in the 3xTG-AD mice by an apparent increase in size and process number. Another glial marker, S100, was expressed by astrocytes in both the non-transgenic (NTG) controls and 3xTG-AD retinas. Labeling was predominantly nuclear in nine month non-transgenic (NTG) control mice but was also seen in the cytoplasm and processes at 18 months of age. Interestingly, the nuclear localization was not as prominent in the 3xTG-AD retina even at nine months with labeling observed in astrocyte processes. The diffusion of S100 suggests the possible secretion of this protein, as is seen in the brain, with age and, more profoundly, associated with AD. Several dense, abnormally shaped, opaque structures were noted in all 3xTG-AD mice investigated. These structures, which were enveloped by GFAP and S100-positive astrocytes and Müller cells, were positive for amyloid beta, suggesting that they are amyloid plaques. Staining control retinas with amyloid showed similar structures in 30% of NTG animals but these were fewer in number and not associated with glial activation. The results herein indicate retinal glia activation in the 3xTG-AD mouse retina.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins Hospital, M023 Smith Building, 400 N. Broadway, Baltimore, MD 21287, USA. Electronic address: medwar28@jhmi.edu.
authors.forename: Malia M
authors.initials: MM
authors.lastname: Edwards
authors.affiliation: Department of Neurosciences, University of Basque Country, UPV/EHU, Leioa, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. Electronic address: j.rodriguez-arellano@ikerbasque.org.
authors.forename: José J
authors.initials: JJ
authors.lastname: Rodríguez
authors.affiliation: Department of Neurosciences, University of Basque Country, UPV/EHU, Leioa, Spain. Electronic address: raquel.gutierrezlanza@gmail.com.
authors.forename: Raquel
authors.initials: R
authors.lastname: Gutierrez-Lanza
authors.affiliation: Wilmer Eye Institute, Johns Hopkins Hospital, M023 Smith Building, 400 N. Broadway, Baltimore, MD 21287, USA. Electronic address: J.R.Yates@exeter.ac.uk.
authors.forename: Joseph
authors.initials: J
authors.lastname: Yates
authors.affiliation: Department of Neurosciences, University of Basque Country, UPV/EHU, Leioa, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK. Electronic address: Alexej.Verkhratsky@manchester.ac.uk.
authors.forename: Alexei
authors.initials: A
authors.lastname: Verkhratsky
authors.affiliation: Wilmer Eye Institute, Johns Hopkins Hospital, M023 Smith Building, 400 N. Broadway, Baltimore, MD 21287, USA. Electronic address: glutty1@jhmi.edu.
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Lutty
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000378:metabolism / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D055351:Retinal Neurons / Q000166:cytology*; D009418:S100 Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; C558298:Mapt protein, mouse; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D009418:S100 Proteins; C528900:glial fibrillary astrocytic protein, mouse; C580804:presenilin 1, mouse; D016875:tau Proteins
keywords: Alzheimer's disease; GFAP; Müller cells; astrogliosis; retina