Abstract
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.
Abbreviations:
- 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