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Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Microglial alterations in human Alzheimer's disease following Aβ42 immunization
E Zotova1, C Holmes, D Johnston
1Division of Clinical Neurosciences, School of Medicine, University of Southampton, UK. e.zotova@soton.ac.uk
Aims:
In Alzheimer's disease (AD), microglial activation prompted by the presence of amyloid has been proposed as an important contributor to the neurodegenerative process. Conversely following Aβ immunization, phagocytic microglia have been implicated in plaque removal, potentially a beneficial effect. We have investigated the effects of Aβ42 immunization on microglial activation and the relationship with Aβ42 load in human AD.
Methods:
Immunostaining against Aβ42 and microglia (CD68 and HLA-DR) was performed in nine immunized AD cases (iAD - AN1792, Elan Pharmaceuticals) and eight unimmunized AD (cAD) cases.
Results:
Although the Aβ42 load (% area stained of total area examined) was lower in the iAD than the cAD cases (P=0.036), the CD68 load was higher (P=0.046). In addition, in the iAD group, the CD68 level correlated with the Aβ42 load, consistent with the immunization upregulating microglial phagocytosis when plaques are present. However, in two long-surviving iAD patients in whom plaques had been extensively cleared, the CD68 load was less than in controls. HLA-DR quantification did not show significant difference implying that the microglial activation may have related specifically to their phagocytic function. CD68 and HLA-DR loads in the pons were similar in both groups, suggesting that the differences in microglial activation in the cortex were due to the presence of AD pathology.
Conclusion:
Our findings suggest that Aβ42 immunization modifies the function of microglia by increasing their phagocytic activity and when plaques have been cleared, the level of phagocytosis is decreased below that seen in unimmunized AD.
Insights
Alzheimer's disease (AD) immunization increases microglial phagocytosis of amyloid plaques. Microglial activity decreases when plaques are cleared, suggesting modified immune responses in AD patients.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglial activation in Alzheimer's disease (AD) is linked to neurodegeneration.
- Amyloid-beta (Aβ) immunization may promote beneficial microglial plaque removal.
Purpose of the Study:
- Investigate Aβ42 immunization effects on microglial activation in human AD.
- Correlate microglial activation with Aβ42 load post-immunization.
Main Methods:
- Immunohistochemistry for Aβ42, CD68, and HLA-DR in immunized (iAD) and control (cAD) AD cases.
- Quantification of Aβ42 and microglial markers in brain tissue.
Main Results:
- Lower Aβ42 load in iAD cases compared to cAD.
- Higher CD68 load (marker of phagocytosis) in iAD cases, correlating with Aβ42 load.
- Reduced CD68 load in long-term survivors with cleared plaques.
Conclusions:
- Aβ42 immunization enhances microglial phagocytic activity in AD.
- Microglial phagocytosis decreases upon plaque clearance, indicating a dynamic immune response.
- Observed microglial activation is specific to cortical AD pathology.
