Alzheimer?s disease (AD) is a rapidly-growing and serious worldwide malady, which is currently the most common cause of dementia in patients of advanced age. Patients develop brain pathology mediated by the amyloid ? (A?) protein, the function of which has recently been reported to include a type of host defense against microbial invaders of the brain, as part of the innate immune response. One component of the innate immune response that is important against microbial infections is the MR1/MAIT cell axis. MR1 is a major histocompatibility complex class I-like molecule that presents microbial vitamin B-derived metabolites to an invariant T cell subpopulation called, ?mucosal-associated invariant T (MAIT) cells?. We have found that MR1 gene expression is upregulated in the temporal cortex of both AD patients and 8-month old 5XFAD (AD model) mice. Moreover, MAIT cells can be found in the brains of normal, wildtype mice. The MR1 protein is expressed on the surface of astrocytes and microglia isolated from the brain, and each cell type is capable of presenting microbial antigens that activate MAIT cells in an MR1-dependent manner. Considering the variety of studies that have reported defects in the blood-brain barrier in the elderly, AD patients and AD mouse models, along with the presence of infectious agents in the AD brain and putative anti-microbial role for A?, we are focused on understanding the role of the MR1/MAIT cell axis in AD pathology development. For this, we will use the 5XFAD AD mouse model system. Our hypothesis is that the MR1/MAIT cell axis contributes to AD pathology. As a result, we predict that in an MR1-deficient environment (i.e., MR1 knockout 5XFAD mice), there will be an attenuation of AD symptoms. To address this hypothesis, we have proposed the following two Specific Aims: 1. Determine the functional capacity of brain cells from 5XFAD mice to stimulate MAIT cells in an MR1-restricted manner; 2. Define AD development in MR1-deficient 5XFAD mice. These studies will allow us to determine the contribution of the MR1/MAIT cell axis in AD development, using this mouse model. We then will use what we learn here as a springboard to the development of more in-depth mechanistic studies, focused on role of this innate immune axis in AD.
The elderly, especially Alzheimer?s disease patients, are more susceptible to bacterial infections. This may be due to the stimulation of certain immune cells. Our goal in this application is to study how the immune system contributes to Alzheimer?s disease development and its response to changes in bacteria that normally reside in the body.
