The role of tau in excitotoxicity

Abstract

Stroke is a leading cause of death. 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 (=penumbra). A major pathomechanism underlying penumbra formation is excitotoxicity, which results from over-excitation of glutaminergic synapses involving N-methyl-D-aspartate receptor signaling. Excitotoxicity also contributes to neurodegeneration in Alzheimer’s disease (AD), where the microtubule-associated protein tau deposits in neurons. Here, I show that reducing tau levels can prevent deficits in different AD mouse models. Furthermore, I show that tau-deficient mice (tau-/-) are protected from excitotoxic brain damage following induced seizure and stroke by middle cerebral artery occlusion and from progression of neurological deficits. Gene profiling indicated differential mitogen-activated protein kinase (MAPK) signaling induced by excitotoxic stress in tau-/- mice, with absent Ras and subsequent extracellular signal-regulated kinase (ERK) activation and immediate early gene induction. Accordingly, inhibition of MAP/ERK kinase 1/2 reduced MCAO-induced infarct size and neurological deficits in wild-type mice to the same degree as tau-depletion. Hence, my findings 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