title: IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior.
abstract: Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer's disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis.
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: pchakrabarty@ufl.edu.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakrabarty
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos-Diaz
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Eddy
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
authors.forename: Cory C
authors.initials: CC
authors.lastname: Funk
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Moore
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: DiNunno
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Awilda M
authors.initials: AM
authors.lastname: Rosario
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Cruz
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Verbeeck
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sacino
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nix
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Janus
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue N, Seattle, WA 98109, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Price
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA. Electronic address: tgolde@ufl.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007162:Immunoproteins / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000276:immunology / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000276:immunology / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C556062:IL10 protein, mouse; D007162:Immunoproteins; D016753:Interleukin-10