title: T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.
abstract: Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer's disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease.
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren, Wagistrasse 12, 8952, Switzerland. Electronic address: mariateresa.ferretti@bli.uzh.ch.
authors.forename: M T
authors.initials: MT
authors.lastname: Ferretti
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren, Wagistrasse 12, 8952, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Merlini
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren, Wagistrasse 12, 8952, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Späni
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren, Wagistrasse 12, 8952, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Gericke
authors.affiliation: Neurology, Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich, Sternwartstrasse 14, 8006 Zurich, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Schweizer
authors.affiliation: Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Enzmann
authors.affiliation: Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Engelhardt
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren, Wagistrasse 12, 8952, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Kulic
authors.affiliation: Neurology, Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich, Sternwartstrasse 14, 8006 Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Suter
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Schlieren, Wagistrasse 12, 8952, Switzerland.
authors.forename: R M
authors.initials: RM
authors.lastname: Nitsch
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000473:pathology; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D010641:Phenotype; D058225:Plaque, Amyloid; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines
keywords: Alzheimer’s disease; Amyloid-beta peptide; Interferon gamma; MHC-II; T-cell