Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy.

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

Omega-3 polyunsaturated fatty acids suppress metastatic features of human cholangiocarcinoma cells by suppressing twist.

Cholangiocarcinoma (CCA) is a highly malignant cancer of the bile duct, which has a five-year survival rate less than 5% due to a high metastasis rate and lack of therapeutic options. Although omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to inhibit the proliferation of CCA cells, the effects on CCA metastasis have not been previously reported. In this study, we first assessed the proliferation, migration and invasion effects of n-3 PUFA-based fish oil on human CCA cells. Then, we investigated PUFA effects on metastasis in vivo by xenografting CCA cells into zebrafish larvae that overexpress a critical n-3 PUFA synthesis gene, Δ6 fatty acid desaturase. The results indicated that n-3 PUFA-based fish oil suppresses CCA cell growth, potentially by blocking the cell cycle at G2/M phase, and it inhibits migration and invasion potential with coincident downregulation of migration-related genes. Furthermore, zebrafish endogenous n-3 PUFAs appear to suppress CCA metastasis by inhibiting the expression of twist, a key regulator of tumor metastasis. Interestingly, only long chain n-3 PUFAs could inhibit the expression of twist in CCA cells. Together, our results suggest that n-3 PUFAs, especially DHA, may inhibit proliferation and metastasis of CCA cells by inhibiting the expression of twist.