Neuroimmune Genomic Profiling of Alzheimer's Disease

Summary Molecular-genetic studies have illuminated the primary pathway of Alzheimer’s disease (AD). However, a relatively long chronic prodromal period of the disease, and the cascade of molecular events underlying the AD-associated synaptic and neuronal loss and neurodegeneration in the aging brain, have not yet been fully

elucidated. Aging is the most common risk factor contributing to the decline of both the immune system and brain function. Recently, we, and others, demonstrated that, surprisingly, the adaptive immune system is involved in Alzheimer’s disease. As this is a newly emergent field, the molecular mechanisms of interactions between

adaptive immunity and AD remains unknown. We hypothesize that harmful populations of γδT-cells or brain- infiltrating αβT-cells (CD8+ T-cells) responding to aberrantly expressed antigens in the brain contribute to AD pathology. In our recent report and in our preliminary data, we found that the depletion of B-cells or T-cells (

CD8+ T cells) in AD model mice reduces AD-associated pathology. Although we, and others, detected the T- cells in the human and mouse brain, the hypervariable immunogene TCR-repertoires and molecular identities of populations of T-cells in the brain have not yet been determined. This implies that the origin and functional

connections of adaptive immune and brain cells remain unknown. We have developed and applied highly sensitive assays to track TCR repertoires in AD patients versus controls. On the other hand, we found highly increased epigenomic chromatin accessibility and upregulation of adaptive immune response genes (MHC

complex and other genes) in the neuronal and non-neuronal residential cells in the AD brain. We will apply large-scale, innovative, high-throughput genomic technologies for the analysis of AD-mouse models and a large collection of clinically characterized brain specimens from both AD and non-demented subjects. We will

conduct a molecular dissection of the neuronal- adaptive immune- genomic axis to identify novel integrative factors contributing to AD pathogenesis or to the protection of brain neurons in the aging process.