Selective Knocking out of FynT‐isoform‐attenuated Tau Pathology, Synaptic Degeneration and Neuroinflammation in P301S Mutant Human Tau Transgenic Mouse Model

AbstractBackgroundAccumulating data demonstrate that Fyn tyrosine kinase is involved in oligomeric amyloid‐β toxicity and tau pathology in Alzheimer's disease (AD). We reported that selective up‐regulation of FynT isoform in post‐mortem AD brains was associated with tau pathology and neuroinflammation (Lee et al., 2016). Furthermore, our preliminary data demonstrated that FynT induction could be recapitulated in aged P301S mutant human tau transgenic mice, which also correlated significantly with tau pathology and neuroinflammation. We thus hypothesize that FynT could be the pathogenic isoform of Fyn in AD. In this study, we generate double transgenic model by knocking out FynT in P301S mice and monitor the possible protective effects on disease progression.MethodFynT‐knockout (KO) is a transgenic model with specific knockdown of FynT isoform but retains FynB expression. Double transgenic mice (DTg) have been generated by crossing KO with P301S mutant human tau transgenic mice. HTRF technology‐based Cisbio assay kits, real‐time RT‐PCR and immunoblots are used to monitor changes of tau pathology, neuroinflammation and synaptic markers in the brains, respectively.ResultSubsequent studies were conducted and analyzed in males because we noticed that P301S males significantly manifested more severe tau pathology and neuroinflammation than P301S females. Significant decrease of phosphorylated tau, aggregated tau and GFAP expression were detected in DTg when compared with P301S. Consistently, reduction of synaptic markers in P301S mice can also be rescued by depletion of FynT in DTg.ConclusionSelective knocking out of FynT isoform led to the attenuation of tau pathology, neuroinflammation and synaptic degeneration in mice with P301S background. This suggests that FynT could be the pathogenic isoform of Fyn in AD. This study further ascertains the isoform‐specific role of FynT as a therapeutic target for AD.