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Microglial immunophenotype in dementia with Alzheimer’s pathology

Microglial immunophenotype in dementia with Alzheimer’s pathology
Microglial immunophenotype in dementia with Alzheimer’s pathology
Background: Genetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes.

Methods: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer’s pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for CD68 (phagocytosis), HLA-DR (antigen presenting function), Iba1 (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fc??receptor I).

Results: The presence of dementia was associated positively with CD68 (P<0.001), MSR-A (P=0.010) and CD64 (P=0.007), and negatively with Iba1 (P<0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination, was associated positively with Iba1 (P<0.001) and negatively with CD68 (P=0.033), and in participants with dementia and Alzheimer’s pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia the relationship with Alzheimer’s pathology was negative or not significant, and positive in participants with dementia and Alzheimer’s pathology. APOE ?2 allele was associated with expression of Iba1 (P=0.001) and MSR-A (P<0.001) and APOE ?4 with CD68, HLA-DR and CD64 (P<0.001).

Conclusion: Our findings raise the possibility that in dementia with Alzheimer’s pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to A? and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.
1742-2094
1-10
Minett, Thais
57b495a8-8be2-4757-a3c9-413acbb60b80
Classey, John
193d01fb-df0b-4b0a-a098-5fd6a59c3e7a
Matthews, Fiona E.
59ac64aa-aebc-4502-ae70-0feffb5aa3f1
Fahrenhold, Marie
58ddee6a-20b3-4be8-9b87-69d617e639fd
Taga, Mariko
7d141f5d-087a-4439-8148-4f99307bc6e4
Brayne, Carol
978cfad1-c7f6-4f79-aa1c-4f189eaaf035
Ince, Paul G.
c1b8f33a-238f-46ae-8edc-da2594c53e48
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Minett, Thais
57b495a8-8be2-4757-a3c9-413acbb60b80
Classey, John
193d01fb-df0b-4b0a-a098-5fd6a59c3e7a
Matthews, Fiona E.
59ac64aa-aebc-4502-ae70-0feffb5aa3f1
Fahrenhold, Marie
58ddee6a-20b3-4be8-9b87-69d617e639fd
Taga, Mariko
7d141f5d-087a-4439-8148-4f99307bc6e4
Brayne, Carol
978cfad1-c7f6-4f79-aa1c-4f189eaaf035
Ince, Paul G.
c1b8f33a-238f-46ae-8edc-da2594c53e48
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61

Minett, Thais, Classey, John, Matthews, Fiona E., Fahrenhold, Marie, Taga, Mariko, Brayne, Carol, Ince, Paul G., Nicoll, James and Boche, Delphine (2016) Microglial immunophenotype in dementia with Alzheimer’s pathology. Journal of Neuroinflammation, 13 (135), 1-10. (doi:10.1186/s12974-016-0601-z). (PMID:27256292)

Record type: Article

Abstract

Background: Genetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes.

Methods: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer’s pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for CD68 (phagocytosis), HLA-DR (antigen presenting function), Iba1 (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fc??receptor I).

Results: The presence of dementia was associated positively with CD68 (P<0.001), MSR-A (P=0.010) and CD64 (P=0.007), and negatively with Iba1 (P<0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination, was associated positively with Iba1 (P<0.001) and negatively with CD68 (P=0.033), and in participants with dementia and Alzheimer’s pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia the relationship with Alzheimer’s pathology was negative or not significant, and positive in participants with dementia and Alzheimer’s pathology. APOE ?2 allele was associated with expression of Iba1 (P=0.001) and MSR-A (P<0.001) and APOE ?4 with CD68, HLA-DR and CD64 (P<0.001).

Conclusion: Our findings raise the possibility that in dementia with Alzheimer’s pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to A? and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.

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Accepted/In Press date: 26 May 2016
e-pub ahead of print date: 2 June 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 395477
URI: https://eprints.soton.ac.uk/id/eprint/395477
ISSN: 1742-2094
PURE UUID: 075caea1-e65a-4b59-b149-b53710bbf167
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

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Date deposited: 31 May 2016 10:50
Last modified: 10 Dec 2019 06:31

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Contributors

Author: Thais Minett
Author: John Classey
Author: Fiona E. Matthews
Author: Marie Fahrenhold
Author: Mariko Taga
Author: Carol Brayne
Author: Paul G. Ince
Author: James Nicoll ORCID iD
Author: Delphine Boche ORCID iD

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