P2‐086: FYN Expression and Regulatory Region Genetic Variation

Tau phosphorylation is under the control of multiple kinases and phosphatases, including GSK3β, Fyn, and PP2A. Previously, our group correlated two regulatory region single nucleotide polymorphisms (SNPs) in the FYN gene as associated with increased hyperphosphorylated tau levels. In this study, we hypothesized that FYN expression in the brain is directly influenced by AD status and genetic content. Brain samples of cerebellum and hippocampus were taken from patients with late-onset AD (n = 21) and cognitively normal controls (n = 22), and were analyzed for FYN mRNA and protein expression based on disease status and regulatory region SNPs. Additionally, FYN promoter-3' UTR haplotype constructs were expressed in human cell lines and analyzed for FYN promoter activity. Our results suggest that FYN hippocampal mRNA levels stay constant but protein levels are increased in AD patients, which are further altered by regulatory SNPs. Additionally, expression of the FYN 3’ UTR can inhibit promoter activity in multiple human cell lines, suggesting regulatory region variation can play an important role in FYN modulation. Further study supports a potential role for microRNAs participating in regulatory roles of FYN expression. Together, these data suggest that FYN expression is regulated according to AD status and promoter haplotype, and genetic variants may be instrumental in the development of NFTs in AD and other tauopathies.