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Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization

Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization
Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization
Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-β immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-β42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-β and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-?42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-β42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-β immunization, the microglial functional state is altered in association with reduced amyloid-β and tau pathology. The results suggest that, in the long term, amyloid-β immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.
alzheimer’s disease, microglia, immunotherapy, innate immunity, clinical trial
0006-8950
2677-2696
Zotova, E.
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Bharambe, V.
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Cheaveau, M.
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Morgan, W.
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Holmes, C.
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Harris, Scott
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Neal, J.W.
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Love, S.
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Nicoll, J.A.R.
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Boche, D.
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Zotova, E.
3558dd45-67a7-4e7a-b2ef-a9155ca784e8
Bharambe, V.
0b8853fc-ba71-4ceb-a153-3b614422ed66
Cheaveau, M.
09e708c5-1bce-4a23-842e-3a6b926a0e3f
Morgan, W.
b6aad7a8-9954-4e6e-8f71-d90890117ba0
Holmes, C.
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Harris, Scott
19ea097b-df15-4f0f-be19-8ac42c190028
Neal, J.W.
e10f04af-1a50-4aab-a29d-69a5adcaf423
Love, S.
de3ec24d-be42-4ca4-967d-b05436b6adc9
Nicoll, J.A.R.
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Boche, D.
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Zotova, E., Bharambe, V., Cheaveau, M., Morgan, W., Holmes, C., Harris, Scott, Neal, J.W., Love, S., Nicoll, J.A.R. and Boche, D. (2013) Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization. Brain, 136 (9), 2677-2696. (doi:10.1093/brain/awt210). (PMID:23943781)

Record type: Article

Abstract

Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-β immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-β42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-β and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-?42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-β42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-β immunization, the microglial functional state is altered in association with reduced amyloid-β and tau pathology. The results suggest that, in the long term, amyloid-β immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.

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Published date: 13 August 2013
Keywords: alzheimer’s disease, microglia, immunotherapy, innate immunity, clinical trial
Organisations: Faculty of Medicine

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Local EPrints ID: 353738
URI: http://eprints.soton.ac.uk/id/eprint/353738
ISSN: 0006-8950
PURE UUID: 1b2c286b-d3e5-4c20-81e2-f37698ad3ebf
ORCID for C. Holmes: ORCID iD orcid.org/0000-0003-1999-6912
ORCID for J.A.R. Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for D. Boche: ORCID iD orcid.org/0000-0002-5884-130X

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Date deposited: 17 Jun 2013 09:09
Last modified: 18 Feb 2021 16:59

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Contributors

Author: E. Zotova
Author: V. Bharambe
Author: M. Cheaveau
Author: W. Morgan
Author: C. Holmes ORCID iD
Author: Scott Harris
Author: J.W. Neal
Author: S. Love
Author: J.A.R. Nicoll ORCID iD
Author: D. Boche ORCID iD

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