Lamivudine (3TC), a nucleoside reverse transcriptase inhibitor, prevents the neuropathological alterations present in mutant tau transgenic mice

Abstract

The dysregulation of transposable elements contributes to neurodegenerative disorders. Previous studies have reported an increase in retrotransposon transcription in Drosophila models, as well as in human tauopathies. In this context, here we tested the possible protective effects of a reverse transcriptase inhibitor, namely lamivudine (also known as 3TC), in P301S mice, an animal model of Alzheime[r]s disease based on FTDP-17-tau overexpression. Transgenic P301S mice administered lamivudine through drinking water showed a decrease in the following histopathological marks typical of tauopathies: tau phosphorylation; inflammation; neuronal death; and hippocampal atrophy. Lamivudine treatment attenuated motor deficits (Rotarod test) and improved short-term memory (Y-maze test). To evaluate the role of tau in retrotransposition, we cotransfected HeLa cells with a plasmid containing a complete LINE-1 sequence and a neomycin reporter cassette designed for retrotransposition assays, and a plasmid with the tau sequence. LINE-1 insertion increased considerably in the cotransfection compared to the transfection without tau. In addition, lamivudine inhibited the insertion of LINE-1. Our data suggest that the progression of the tauopathy can be attenuated by the administration of lamivudine upon the first symptoms of neuropathology. HighlightsO_LILamivudine treatment in drinking water inhibited a tau-associated pathology in a mouse model of tauopathy. C_LIO_LITau promotes the insertion of transposable elements LINE-1 in vitro. LINE-1 insertion in vitro is inhibited by lamivudine. C_LIO_LILamivudine attenuates memory and motor deficits in tau transgenic mice. C_LI