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The role of microglia in Alzheimer's disease and following amyloid-beta-42 (A?42) immunisation

The role of microglia in Alzheimer's disease and following amyloid-beta-42 (A?42) immunisation
The role of microglia in Alzheimer's disease and following amyloid-beta-42 (A?42) immunisation
Inflammation is recognised as an important contributor to Alzheimer's disease (AD) pathogenesis alongside extracellular deposits of amyloid β protein (Aβ) and intraneuronal deposits of hyper-phosphorylated tau protein. Microglia are the key component of innate immunity within the central nervous system, and the source of inflammation in the brain. The amyloid cascade hypothesis places Aβ at a key point in the pathogenesis of AD. Consequently, immunisation against Aβ is a promising experimental treatment for AD. The current study presents a neuropathological follow-up of a unique cohort of AD patients who took part in the active Aβ42 immunisation clinical trial (AN1792, Elan) and in whom reduction in Aβ load had been observed. The hypothesis of the study is that Aβ42 immunisation affects the microglial activation level and profile associated with the reduction in Aβ.

Levels of the microglial markers indicative of specific microglial functions, the microglial receptors involved in antigen recognition and uptake, complement component C1q, IgG, Aβ42 and phospho-tau in the brain tissue (frontal, temporal and parietal lobes) of immunised (n=11) and non-immunised (n=28) AD patients were analysed using immunohistochemistry. In immunised brain, a two-fold reduction in Fc receptor I (P=0.001) and Fcγ receptor II (P=0.002), a ten-fold reduction in macrophage scavenger receptor A (P <0.001), and a 40% reduction in lysosomal glycoprotein CD68 (P=0.018) compared to non-immunised brain were observed. Similarly, Aβ42 and phospho-tau levels were also decreased by 80% and 40% respectively. No changes in the microglial activation and antigen-presentation receptor HLA-DR, calcium-adapter channel Iba-1, or the levels of IgG and C1q were detected. The load of all microglial markers, IgG and C1q correlated with the phospho-tau load in non-immunised cases. In addition, Iba-1 and Fc RII load inversely correlated with Aβ42 load in the non-immunised group.

These correlations no longer held in the immunised group. Instead, a positive correlation between the number of MSR-A positive microglial clusters and Aβ42, and an inverse correlation between C1q and Aβ42 were noted in immunised AD cases.

The current study is the first of its kind in presenting a detailed immunohistochemical profile of microglia in human AD and following active A?42 immunisation treatment. In addition, a consistent and reproducible method for automated microscopy image analysis was developed as part of this project contributing to research methodologies. The results support the changes in the level and profile of microglial activation implied by the hypothesis. The data also suggest a link between immune system activation and the tau pathology in AD. The ability of microglia to change their profile and switch targets following stimulation by active immunisation is demonstrated in human brain.
Zotova, Elina
3558dd45-67a7-4e7a-b2ef-a9155ca784e8
Zotova, Elina
3558dd45-67a7-4e7a-b2ef-a9155ca784e8
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61

Zotova, Elina (2012) The role of microglia in Alzheimer's disease and following amyloid-beta-42 (A?42) immunisation. University of Southampton, Faculty of Medicine, Doctoral Thesis, 260pp.

Record type: Thesis (Doctoral)

Abstract

Inflammation is recognised as an important contributor to Alzheimer's disease (AD) pathogenesis alongside extracellular deposits of amyloid β protein (Aβ) and intraneuronal deposits of hyper-phosphorylated tau protein. Microglia are the key component of innate immunity within the central nervous system, and the source of inflammation in the brain. The amyloid cascade hypothesis places Aβ at a key point in the pathogenesis of AD. Consequently, immunisation against Aβ is a promising experimental treatment for AD. The current study presents a neuropathological follow-up of a unique cohort of AD patients who took part in the active Aβ42 immunisation clinical trial (AN1792, Elan) and in whom reduction in Aβ load had been observed. The hypothesis of the study is that Aβ42 immunisation affects the microglial activation level and profile associated with the reduction in Aβ.

Levels of the microglial markers indicative of specific microglial functions, the microglial receptors involved in antigen recognition and uptake, complement component C1q, IgG, Aβ42 and phospho-tau in the brain tissue (frontal, temporal and parietal lobes) of immunised (n=11) and non-immunised (n=28) AD patients were analysed using immunohistochemistry. In immunised brain, a two-fold reduction in Fc receptor I (P=0.001) and Fcγ receptor II (P=0.002), a ten-fold reduction in macrophage scavenger receptor A (P <0.001), and a 40% reduction in lysosomal glycoprotein CD68 (P=0.018) compared to non-immunised brain were observed. Similarly, Aβ42 and phospho-tau levels were also decreased by 80% and 40% respectively. No changes in the microglial activation and antigen-presentation receptor HLA-DR, calcium-adapter channel Iba-1, or the levels of IgG and C1q were detected. The load of all microglial markers, IgG and C1q correlated with the phospho-tau load in non-immunised cases. In addition, Iba-1 and Fc RII load inversely correlated with Aβ42 load in the non-immunised group.

These correlations no longer held in the immunised group. Instead, a positive correlation between the number of MSR-A positive microglial clusters and Aβ42, and an inverse correlation between C1q and Aβ42 were noted in immunised AD cases.

The current study is the first of its kind in presenting a detailed immunohistochemical profile of microglia in human AD and following active A?42 immunisation treatment. In addition, a consistent and reproducible method for automated microscopy image analysis was developed as part of this project contributing to research methodologies. The results support the changes in the level and profile of microglial activation implied by the hypothesis. The data also suggest a link between immune system activation and the tau pathology in AD. The ability of microglia to change their profile and switch targets following stimulation by active immunisation is demonstrated in human brain.

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Published date: December 2012
Organisations: University of Southampton, Faculty of Medicine

Identifiers

Local EPrints ID: 347858
URI: http://eprints.soton.ac.uk/id/eprint/347858
PURE UUID: 316c82a1-bbb6-4a5f-9501-c90ddef0380f
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

Catalogue record

Date deposited: 28 Feb 2013 14:43
Last modified: 12 Dec 2019 01:37

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Contributors

Author: Elina Zotova
Thesis advisor: James Nicoll ORCID iD
Thesis advisor: Delphine Boche ORCID iD

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