Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization
Alzheimer's disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain a...
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todo:paper_10509631_v26_n2_p194_Pomilio2023-10-03T16:00:29Z Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization Pomilio, C. Pavia, P. Gorojod, R.M. Vinuesa, A. Alaimo, A. Galvan, V. Kotler, M.L. Beauquis, J. Saravia, F. AD Astrocytes Hilus LC3 Microglia Neuroinflammation Stratum radiatum Ubiquitin amyloid beta protein cell protein congo red Iba1 protein protein p62 ubiquitin unclassified drug amyloid beta protein Alzheimer disease amyloid plaque animal cell animal experiment animal model animal tissue Article astrocyte autophagy cell density cell volume controlled study dentate gyrus disease course glia hippocampus immunofluorescence immunohistochemistry immunoreactivity in vitro study internalization light chain macroglia microglia mouse neuropathology nonhuman priority journal protein degradation protein processing rat senescence stratum radiatum transgenic mouse Alzheimer disease animal autophagy C57BL mouse cell culture disease model glia metabolism pathology physiology tumor cell line Alzheimer Disease Amyloid beta-Peptides Animals Autophagy Cell Line, Tumor Cells, Cultured Dentate Gyrus Disease Models, Animal Mice Mice, Inbred C57BL Mice, Transgenic Neuroglia Rats Alzheimer's disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain areas involved could help to design new successful treatments. Hence, we studied early alterations of hippocampal glia and their progression during the neuropathology in PDAPP-J20 transgenic mice, AD model, at 3, 9, and 15 months (m) of age. At 3 m, before deposits formation, microglial Iba1+ cells from transgenic mice already exhibited signs of activation and larger soma size in the hilus, alterations appearing later on stratum radiatum. Iba1 immunohistochemistry revealed increased cell density and immunoreactive area in PDAPP mice from 9 m onward selectively in the hilus, in coincidence with prominent amyloid Congo red+deposition. At pre-plaque stages, GFAP+ astroglia showed density alterations while, at an advanced age, the presence of deposits was associated with important glial volume changes and apparently being intimately involved in amyloid degradation. Astrocytes around plaques were strongly labeled for LC3 until 15 m in Tg mice, suggestive of increased autophagic flux. Moreover, β-Amyloid fibrils internalization by astrocytes in in vitro conditions was dependent on autophagy. Co-localization of Iba1 with ubiquitin or p62 was exclusively found in microglia contacting deposits from 9 m onward, suggesting torpid autophagy. Our work characterizes glial changes at early stages of the disease in PDAPP-J20 mice, focusing on the hilus as an especially susceptible hippocampal subfield, and provides evidence that glial autophagy could play a role in amyloid processing at advanced stages. © 2016 Wiley Periodicals, Inc. Fil:Alaimo, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Kotler, M.L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_10509631_v26_n2_p194_Pomilio |
institution |
Universidad de Buenos Aires |
institution_str |
I-28 |
repository_str |
R-134 |
collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
topic |
AD Astrocytes Hilus LC3 Microglia Neuroinflammation Stratum radiatum Ubiquitin amyloid beta protein cell protein congo red Iba1 protein protein p62 ubiquitin unclassified drug amyloid beta protein Alzheimer disease amyloid plaque animal cell animal experiment animal model animal tissue Article astrocyte autophagy cell density cell volume controlled study dentate gyrus disease course glia hippocampus immunofluorescence immunohistochemistry immunoreactivity in vitro study internalization light chain macroglia microglia mouse neuropathology nonhuman priority journal protein degradation protein processing rat senescence stratum radiatum transgenic mouse Alzheimer disease animal autophagy C57BL mouse cell culture disease model glia metabolism pathology physiology tumor cell line Alzheimer Disease Amyloid beta-Peptides Animals Autophagy Cell Line, Tumor Cells, Cultured Dentate Gyrus Disease Models, Animal Mice Mice, Inbred C57BL Mice, Transgenic Neuroglia Rats |
spellingShingle |
AD Astrocytes Hilus LC3 Microglia Neuroinflammation Stratum radiatum Ubiquitin amyloid beta protein cell protein congo red Iba1 protein protein p62 ubiquitin unclassified drug amyloid beta protein Alzheimer disease amyloid plaque animal cell animal experiment animal model animal tissue Article astrocyte autophagy cell density cell volume controlled study dentate gyrus disease course glia hippocampus immunofluorescence immunohistochemistry immunoreactivity in vitro study internalization light chain macroglia microglia mouse neuropathology nonhuman priority journal protein degradation protein processing rat senescence stratum radiatum transgenic mouse Alzheimer disease animal autophagy C57BL mouse cell culture disease model glia metabolism pathology physiology tumor cell line Alzheimer Disease Amyloid beta-Peptides Animals Autophagy Cell Line, Tumor Cells, Cultured Dentate Gyrus Disease Models, Animal Mice Mice, Inbred C57BL Mice, Transgenic Neuroglia Rats Pomilio, C. Pavia, P. Gorojod, R.M. Vinuesa, A. Alaimo, A. Galvan, V. Kotler, M.L. Beauquis, J. Saravia, F. Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization |
topic_facet |
AD Astrocytes Hilus LC3 Microglia Neuroinflammation Stratum radiatum Ubiquitin amyloid beta protein cell protein congo red Iba1 protein protein p62 ubiquitin unclassified drug amyloid beta protein Alzheimer disease amyloid plaque animal cell animal experiment animal model animal tissue Article astrocyte autophagy cell density cell volume controlled study dentate gyrus disease course glia hippocampus immunofluorescence immunohistochemistry immunoreactivity in vitro study internalization light chain macroglia microglia mouse neuropathology nonhuman priority journal protein degradation protein processing rat senescence stratum radiatum transgenic mouse Alzheimer disease animal autophagy C57BL mouse cell culture disease model glia metabolism pathology physiology tumor cell line Alzheimer Disease Amyloid beta-Peptides Animals Autophagy Cell Line, Tumor Cells, Cultured Dentate Gyrus Disease Models, Animal Mice Mice, Inbred C57BL Mice, Transgenic Neuroglia Rats |
description |
Alzheimer's disease (AD) is a progressive neurodegenerative disease without effective therapy. Brain amyloid deposits are classical histopathological hallmarks that generate an inflammatory reaction affecting neuronal and glial function. The identification of early cell responses and of brain areas involved could help to design new successful treatments. Hence, we studied early alterations of hippocampal glia and their progression during the neuropathology in PDAPP-J20 transgenic mice, AD model, at 3, 9, and 15 months (m) of age. At 3 m, before deposits formation, microglial Iba1+ cells from transgenic mice already exhibited signs of activation and larger soma size in the hilus, alterations appearing later on stratum radiatum. Iba1 immunohistochemistry revealed increased cell density and immunoreactive area in PDAPP mice from 9 m onward selectively in the hilus, in coincidence with prominent amyloid Congo red+deposition. At pre-plaque stages, GFAP+ astroglia showed density alterations while, at an advanced age, the presence of deposits was associated with important glial volume changes and apparently being intimately involved in amyloid degradation. Astrocytes around plaques were strongly labeled for LC3 until 15 m in Tg mice, suggestive of increased autophagic flux. Moreover, β-Amyloid fibrils internalization by astrocytes in in vitro conditions was dependent on autophagy. Co-localization of Iba1 with ubiquitin or p62 was exclusively found in microglia contacting deposits from 9 m onward, suggesting torpid autophagy. Our work characterizes glial changes at early stages of the disease in PDAPP-J20 mice, focusing on the hilus as an especially susceptible hippocampal subfield, and provides evidence that glial autophagy could play a role in amyloid processing at advanced stages. © 2016 Wiley Periodicals, Inc. |
format |
JOUR |
author |
Pomilio, C. Pavia, P. Gorojod, R.M. Vinuesa, A. Alaimo, A. Galvan, V. Kotler, M.L. Beauquis, J. Saravia, F. |
author_facet |
Pomilio, C. Pavia, P. Gorojod, R.M. Vinuesa, A. Alaimo, A. Galvan, V. Kotler, M.L. Beauquis, J. Saravia, F. |
author_sort |
Pomilio, C. |
title |
Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization |
title_short |
Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization |
title_full |
Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization |
title_fullStr |
Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization |
title_full_unstemmed |
Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization |
title_sort |
glial alterations from early to late stages in a model of alzheimer's disease: evidence of autophagy involvement in aβ internalization |
url |
http://hdl.handle.net/20.500.12110/paper_10509631_v26_n2_p194_Pomilio |
work_keys_str_mv |
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1782024840216051712 |