Microglial immunophenotype in dementia with Alzheimer's pathology
Thais Minett1,2, John Classey3, Fiona E Matthews4
1Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
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 Fcγ 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) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 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 Aβ 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.
Insights
Microglia, the brain's immune cells, show reduced motility (Iba1) in Alzheimer's disease dementia. Increased expression of other markers (CD68, MSR-A) correlates with pathology and cognitive decline, suggesting complex microglial roles.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Genetic risk factors suggest inflammation is key in Alzheimer's disease (AD).
- Microglia, brain macrophages, survey the brain via motile processes.
Purpose of the Study:
- To investigate microglial roles in dementia with Alzheimer's pathology.
- To immunophenotype microglia in post-mortem brain tissue.
Main Methods:
- Analyzed cerebral cortex from 299 participants using immunohistochemistry.
- Assessed markers: CD68 (phagocytosis), HLA-DR (antigen presentation), Iba1 (motility), MSR-A (plaque phagocytosis), CD64 (Fc receptor).
Main Results:
- Dementia associated with increased CD68, MSR-A, CD64 and decreased Iba1.
- Cognitive function correlated with Iba1 (positively) and CD68 (negatively) in non-demented individuals.
- Alzheimer's pathology linked to microglial markers differently in demented vs. non-demented groups.
- APOE ε2 associated with Iba1/MSR-A; APOE ε4 with CD68/HLA-DR/CD64.
Conclusions:
- Microglia may lose motility (Iba1) in AD dementia, impairing neuronal support.
- Increased microglial clearance markers (CD68, MSR-A) associate with AD pathology and cognitive decline.
- Microglial responses to AD pathology are complex and vary with dementia status, potentially influencing disease development.
