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

Abstract

AbstractBackgroundThe 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 Alzheimer’s disease (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. It is still unknown whether the expression levels of p‐Tau181, p‐Tau217, and p‐Tau231 can be enhanced by physiological LTD induction.MethodYoung adult (2‐3‐months) and aged (17‐18‐months) male Sprague Dawley rats were used in all experiments. Prior to the surgery, animals were anesthetized with urethane (1.5‐1.6 g/kg, i.p.). Field excitatory postsynaptic potentials (EPSPs) were recorded from the stratum radiatum in the CA1 area of left or right hippocampus in response to stimulation of the Schaffer collateral‐commissural pathway. LTD was induced using 1 Hz low frequency stimulation (LFS) consisting of 900 pulses (0.2 ms duration). The rats were sacrificed 30 min post‐LFS. The expression levels of p‐Tau181, p‐Tau217, p‐Tau231, p‐Tau202/205, p‐Tau396, and total tau were analyzed using western blotting and immunofluorescent staining.ResultHere we show that 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. Further, blocking either NMDARs or mGluR5 strongly inhibits the elevation of both p‐Tau181 and p‐Tau217. Finally, targeting ageing with a small molecule cognitive enhancer ISRIB (trans‐isomer) prevents the increase of both p‐Tau181 and p‐Tau217 by LFS in aged rats.ConclusionOur data provide an in vivo means to uncover brain plasticity‐related cellular and molecular processes of tau phosphorylation in health and ageing conditions.