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Tauopathies are a group of neurodegenerative disorders where TAU protein is presented as aggregates or is abnormally phosphorylated, leading to alterations of axonal transport, neuronal death and neuroinflammation. Currently, there is no treatment to slow progression of these diseases. Here, we have investigated whether dimethyl fumarate (DMF), an inducer of the transcription factor NRF2, could mitigate tauopathy in a mouse model. The signaling pathways modulated by DMF were also studied in mouse embryonic fibroblast (MEFs) from wild type or KEAP1-deficient mice. The effect of DMF on neurodegeneration, astrocyte and microglial activation was examined in Nrf2+/+ and Nrf2-/- mice stereotaxically injected in the right hippocampus with an adeno-associated vector expressing human TAUP301L and treated daily with DMF (100mg/kg, i.g) during three weeks. DMF induces the NRF2 transcriptional through a mechanism that involves KEAP1 but also PI3K/AKT/GSK-3-dependent pathways. DMF modulates GSK-3β activity in mouse hippocampi. Furthermore, DMF modulates TAU phosphorylation, neuronal impairment measured by calbindin-D28K and BDNF expression, and inflammatory processes involved in astrogliosis, microgliosis and pro-inflammatory cytokines production. This study reveals neuroprotective effects of DMF beyond disruption of the KEAP1/NRF2 axis by inhibiting GSK3 in a mouse model of tauopathy. Our results support repurposing of this drug for treatment of these diseases.
Pubmed ID: 29121589 RIS Download
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View all literature mentionsThis monoclonal targets Tau
View all literature mentionsThis polyclonal targets Tau (H-150)
View all literature mentionsThis monoclonal targets Phospho-Tau (Ser202, Thr205)
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View all literature mentionsThis polyclonal targets p38 MAPK, phospho (Thr180 / Tyr182)
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis monoclonal targets GSK-3 beta
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (E10) Mouse mAb
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View all literature mentionsThis polyclonal targets CRMP2
View all literature mentionsThis polyclonal targets ACTG1, ACTC1, ACTA1, ACTA2, ACTG2, ACTB
View all literature mentionsThis polyclonal targets Phospho-GSK-3 (Ser9)
View all literature mentionsThis monoclonal targets GADPH
View all literature mentionsThis polyclonal targets GFAP
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473) (193H12) Rabbit mAb
View all literature mentionsThis polyclonal targets Calbindin D28k
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