title: Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
abstract: The role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance ("microglial domain"). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.
authors.affiliation: Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Biomedicina de Malaga (IBIMA), Universidad de Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sanchez-Mejias
authors.affiliation: Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Navarro
authors.affiliation: Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jimenez
authors.affiliation: Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Sanchez-Mico
authors.affiliation: Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Biomedicina de Malaga (IBIMA), Universidad de Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Varo
authors.affiliation: Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Biomedicina de Malaga (IBIMA), Universidad de Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nuñez-Diaz
authors.affiliation: Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Biomedicina de Malaga (IBIMA), Universidad de Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Trujillo-Estrada
authors.affiliation: Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Biomedicina de Malaga (IBIMA), Universidad de Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Davila
authors.affiliation: Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.|Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Marisa
authors.initials: M
authors.lastname: Vizuete
authors.affiliation: Departamento Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Biomedicina de Malaga (IBIMA), Universidad de Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain. vitorica@us.es.|Instituto de Biomedicina de Sevilla (IBiS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, C/Prof. Garcia Gonzalez 2, 41012, Sevilla, Spain. vitorica@us.es.|Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. vitorica@us.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D017493:Leukocyte Common Antigens; D008840:Microfilament Proteins; D053764:Presenilin-1; D058925:Receptors, Purinergic P2Y12; D016875:tau Proteins; C112986:AIF1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C548576:P2RY12 protein, human
keywords: Alzheimer; Hippocampus; Human brain; Microglia; Pathology