title: Glial alterations from early to late stages in a model of Alzheimer's disease: Evidence of autophagy involvement in Aβ internalization.
abstract: 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.
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Instituto De Biologia Y Medicina Experimental Conicet, Buenos Aires, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pomilio
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Instituto De Biologia Y Medicina Experimental Conicet, Buenos Aires, Argentina.
authors.forename: Patricio
authors.initials: P
authors.lastname: Pavia
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, IQUIBICEN-Conicet, Buenos Aires, Argentina.
authors.forename: Roxana Mayra
authors.initials: RM
authors.lastname: Gorojod
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Instituto De Biologia Y Medicina Experimental Conicet, Buenos Aires, Argentina.
authors.forename: Angeles
authors.initials: A
authors.lastname: Vinuesa
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, IQUIBICEN-Conicet, Buenos Aires, Argentina.
authors.forename: Agustina
authors.initials: A
authors.lastname: Alaimo
authors.affiliation: Department of Physiology, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, IQUIBICEN-Conicet, Buenos Aires, Argentina.
authors.forename: Monica Lidia
authors.initials: ML
authors.lastname: Kotler
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Instituto De Biologia Y Medicina Experimental Conicet, Buenos Aires, Argentina.
authors.forename: Juan
authors.initials: J
authors.lastname: Beauquis
authors.affiliation: Departamento De Quimica Biologica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, Instituto De Biologia Y Medicina Experimental Conicet, Buenos Aires, Argentina.
authors.forename: Flavia
authors.initials: F
authors.lastname: Saravia
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides
keywords: AD; LC3; astrocytes; hilus; microglia; neuroinflammation; stratum radiatum; ubiquitin