PLX051875

GSE45703: Tau depletion prevents Ras/ERK-mediated excitotoxic immediate early gene activation and brain damage in stroke

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

Stroke is a leading cause of death1. The majority are ischemic strokes resulting from acute focal brain infarction with sudden and persisting neurological deficits. This primary brain damage is followed by more substantial secondary destruction of surrounding areas, called penumbra. A major pathomechanism underlying penumbra formation is excitotoxicity, which results from over-excitation of glutaminergic synapses involving NMDA receptor (NMDAR) signaling2. Excitotoxicity also contributes to neurodegeneration in Alzheimers disease (AD), where the microtubule-associated protein tau deposits in neurons. We and others have previously shown that reducing tau levels can prevent deficits in different AD mouse models3-5. Here, we show that tau-deficient (tau-/-) mice are protected from excitotoxic brain damage following experimental stroke and from progression of neurological deficits. Gene profiling indicated differential MAPK signaling induced by excitotoxic stress in tau-/- mice, with absent Ras- and subsequent ERK activation and immediate early gene induction. Accordingly, inhibition of MEK1/2-dependent ERK activation reduced MCAO-induced infarct size and neurological deficits in wild-type mice to the same degree as tau-depletion. Hence, our finding suggest tau-dependent Ras/ERK activation drives excitotoxic secondary brain damage in stroke, implicating tau as a possible therapeutic target in acute brain damage beyond AD. SOURCE: Julius Müller (jm-mu@alumni.ethz.ch) - Ernesto Guccione A*Star Singapore