1. T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer's disease-like cerebral amyloidosis.
- Author
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Ferretti MT, Merlini M, Späni C, Gericke C, Schweizer N, Enzmann G, Engelhardt B, Kulic L, Suter T, and Nitsch RM
- Subjects
- Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Amyloidosis pathology, Animals, Antigen Presentation, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Brain metabolism, Cerebral Amyloid Angiopathy metabolism, Cerebral Amyloid Angiopathy pathology, Cytokines metabolism, Dendritic Cells metabolism, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Microglia metabolism, Phenotype, Plaque, Amyloid, T-Lymphocytes metabolism, T-Lymphocytes pathology, Up-Regulation, Alzheimer Disease immunology, Cerebral Amyloid Angiopathy immunology, T-Lymphocytes immunology
- 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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