|Title:||MR1-dependent Amyloid beta pathology in Alzheimer’s Disease|
Johnson, Season, Department of Microbiology and Immunology, Stark Neurosciences Research Institute; Holly N. Kersey, Department of Microbiology and Immunology; Juan F. Codocedo, Stark Neurosciences Research Institute; Kathy L. Newell, Department of Pathology and Laboratory Medicine, Bernardino Ghetti, Stark Neurosciences Research Institute, Department of Pathology and Laboratory Medicine, Department of Neurology; Gary E. Landreth, Stark Neurosciences Research Institute, Department of Anatomy, Cell Biology and Physiology; Bruce T. Lamb, Stark Neurosciences Research Institute, Department of Medical and Molecular Genetics; Adrian L. Oblak, Stark Neurosciences Research Institute, Department of Radiology and Imaging Sciences; Randy R. Brutkiewicz, Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine
Background/Significance/Rationale: The breakdown of the blood-brain barrier, activation of glial cells, and the accumulation of amyloid-beta (Aβ) and neuroinflammation are hallmark features of Alzheimer’s disease (AD). A major producer of inflammation is the mucosal-associated invariant T (MAIT) cell, a type of innate T cell that recognizes the antigen-presenting molecule, MR1. Little is known about the MR1/MAIT cell axis in the brain. This study aims to determine the effects and consequences of the MR1/MAIT cell axis in human and animal models of AD.
Methods: We used the 5XFAD mouse model of AD crossed with MR1 KO mice (which lack both MR1 and MAIT cells) at the 2-, 4-, 6-, and 8-month age time points and human brain tissue from AD and non-AD individuals to identify any correlative relationship between MR1 and Aβ expression. qPCR was used to determine transcriptional changes in Mr1. For the analysis of MR1 and Aβ protein expression in the brain, we used immunofluorescence with antibodies against MR1, microglia, and Aβ.
Results/Findings: Brain MR1 gene and protein expression is increased in both human AD patients and 5XFAD mice. Moreover, MR1 is highly upregulated on microglia that are near Aβ plaques. The expression level of MR1 is positively correlated with that of both IBA1 and Aβ. In contrast, the genetic lack of MR1 in 5XFAD mice reduced Aβ densitometry as well as the diameter of plaques in both the hippocampus and cortex until 8 months of age.
Conclusions/Discussion: MR1 expression affects the temporal development of Ab plaques without altering microglial interaction with plaques. This indicates a potential detrimental role for MR1 in AD pathology.
Translational/Human Health Impact: Understanding the contribution of the MR1/MAIT cell axis could provide new and novel clues as to the role of innate immunity in AD development. This could lead to its identification as a novel therapeutic target in AD.