LTD-inducing low frequency stimulation enhances p-Tau181 and p-Tau217 in an age-dependent manner in live rats

The progressive cognitive decline in Alzheimer’s disease (AD) patients correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of phosphorylated tau (p-Tau) on residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) in cerebrospinal fluid or blood are recently proposed to be particularly sensitive markers of early AD, the generation of p-Tau during brain activity is poorly understood. A major form of synaptic plasticity, long-term depression (LTD), has recently been linked to the enhancement of tau phosphorylation. Here we show that low frequency stimulation (LFS), used to induce LTD, enhances p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 is less sensitive to LFS. Pharmacological antagonism of either NMDA or metabotropic glutamate 5 (mGluR5) receptors inhibits the elevation of both p-Tau181 and p-Tau217. Targeting ageing with a small molecule cognitive enhancer ISRIB (trans-isomer) prevents the enhancement of p-Tau by LFS in aged rats. Together, our data provide an in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation in health and ageing conditions. * AD : Alzheimer’s disease Aβ : amyloid-β protein AβO : Aβ oligomers CSF : cerebrospinal fluid Cdk5 : cyclin-dependent kinase-5 DAPI : 4′,6-diamidino-2-phenylindole DG : dentate gyrus DMSO : dimethyl sulfoxide EPSP : excitatory postsynaptic potential GSK3α : glycogen synthase kinase 3α GSK3β : glycogen synthase kinase 3β HFS : high frequency stimulation i.c.v. : intracerebroventricular ISR : integrated stress response LFS : low frequency stimulation LTD : long-term depression LTP : long-term potentiation mGluR5 : metabotropic glutamate receptor subtype 5 NMDA : N-methyl-D-aspartate NMDAR : N-methyl-D-aspartate receptor PEG400 : polyethylene glycol 400 PMSF : phenylmethylsulfonyl fluoride PrPC : cellular prion protein PVDF : polyvinylidene fluoride p-Tau : phosphorylated tau SDS : sodium dodecyl sulfate TBS-T : tris-buffered saline containing 0.1% Tween 20