PMID- 27256292 OWN - NLM STAT- MEDLINE DCOM- 20170929 LR - 20220310 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 13 IP - 1 DP - 2016 Jun 2 TI - Microglial immunophenotype in dementia with Alzheimer's pathology. PG - 135 LID - 10.1186/s12974-016-0601-z [doi] LID - 135 AB - 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 cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcgamma 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. Apolipoprotein E (APOE) epsilon2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE epsilon4 with CD68, HLA-DR and CD64 (P < 0.001). CONCLUSIONS: 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's pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Abeta 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. FAU - Minett, Thais AU - Minett T AD - Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. AD - Department of Radiology, University of Cambridge, Cambridge, CB2 0QQ, UK. FAU - Classey, John AU - Classey J AD - Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. FAU - Matthews, Fiona E AU - Matthews FE AD - MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, CB2 0SR, UK. FAU - Fahrenhold, Marie AU - Fahrenhold M AD - Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. FAU - Taga, Mariko AU - Taga M AD - Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. FAU - Brayne, Carol AU - Brayne C AD - Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. FAU - Ince, Paul G AU - Ince PG AD - Sheffield Institute for Translational Neuroscience, Sheffield University, Sheffield, S10 2HQ, UK. FAU - Nicoll, James A R AU - Nicoll JA AD - Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. AD - Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, Southampton, SO16 6YD, UK. FAU - Boche, Delphine AU - Boche D AD - Clinical Neurosciences, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. d.boche@soton.ac.uk. CN - MRC CFAS LA - eng GR - G0900582/MRC_/Medical Research Council/United Kingdom GR - G1100540/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00002/12/MRC_/Medical Research Council/United Kingdom GR - G0900652/MRC_/Medical Research Council/United Kingdom GR - G0601022/MRC_/Medical Research Council/United Kingdom GR - G0502157/MRC_/Medical Research Council/United Kingdom GR - G0400074/MRC_/Medical Research Council/United Kingdom GR - G9901400/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20160602 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (AIF1 protein, human) RN - 0 (Antigens, CD) RN - 0 (Antigens, Differentiation, Myelomonocytic) RN - 0 (CD68 antigen, human) RN - 0 (Calcium-Binding Proteins) RN - 0 (Cytokines) RN - 0 (DNA-Binding Proteins) RN - 0 (FCGR1A protein, human) RN - 0 (HLA-DR Antigens) RN - 0 (Microfilament Proteins) RN - 0 (Receptors, IgG) RN - EC 1.8.4.- (Methionine Sulfoxide Reductases) RN - EC 1.8.4.11 (methionine sulfoxide reductase) SB - IM MH - Aged MH - Aged, 80 and over MH - Alzheimer Disease/complications/*pathology MH - Antigens, CD/metabolism MH - Antigens, Differentiation, Myelomonocytic/metabolism MH - Calcium-Binding Proteins MH - Cohort Studies MH - Cytokines/*metabolism MH - DNA-Binding Proteins/*metabolism MH - Dementia/complications/*pathology MH - Diagnosis MH - Female MH - HLA-DR Antigens/metabolism MH - Humans MH - Male MH - Mental Status Schedule MH - Methionine Sulfoxide Reductases/*metabolism MH - Microfilament Proteins MH - Microglia/*metabolism MH - Neuropsychological Tests MH - Receptors, IgG/metabolism PMC - PMC4890505 OTO - NOTNLM OT - Alzheimer's disease OT - Apolipoprotein E OT - Dementia OT - Microglia OT - Neuropathology EDAT- 2016/06/04 06:00 MHDA- 2017/09/30 06:00 PMCR- 2016/06/02 CRDT- 2016/06/04 06:00 PHST- 2016/03/06 00:00 [received] PHST- 2016/05/26 00:00 [accepted] PHST- 2016/06/04 06:00 [entrez] PHST- 2016/06/04 06:00 [pubmed] PHST- 2017/09/30 06:00 [medline] PHST- 2016/06/02 00:00 [pmc-release] AID - 10.1186/s12974-016-0601-z [pii] AID - 601 [pii] AID - 10.1186/s12974-016-0601-z [doi] PST - epublish SO - J Neuroinflammation. 2016 Jun 2;13(1):135. doi: 10.1186/s12974-016-0601-z.