Author:

Abstract:

Alzheimer's disease (AD)is characterized by amyloid deposits and neurofibrillary tangles made of aggregated hyperphosphorylated Tau protein, the latter being correlated with the progression of cognitive deficits. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptors (TrkB) play a critical role in hippocampal synaptic plasticity and memory. BDNF levels are reduced in the hippocampus of AD patients, an effect ascribed to beta-amyloid toxicity. However, whether Tau pathology impacts on BDNF/TrkB signalling is unknown. We have evaluated this relationship using the THY-Tau22 transgenic mice.This model overexpresses a human mutated Tau isoform and exhibits progressive development of hippocampal AD-like Tau pathology together with memory impairments, in the absence of neuronal loss. We demonstrate that the development of Tau pathology is not associated with a major loss of BDNF/TrkB expression. In electrophysiology experiments, however, BDNF increased the slope of field excitatory post-synaptic potentials (fEPSPs) in the stratum radiatum of the CA1 region from WT mice(an index of synaptic facilitation), while it was ineffective in THY-Tau22 mice. In WT slices, co-application of ifenprodil, a selective antagonist of the NR2B subunit of NMDA receptors, abolished BDNF-induced synaptic potentiation of fEPSP, supporting an involvement of NMDAR-dependent signalling in the BDNF effects. Biochemical data indicated that, in THY-Tau22 mice, an alteration of NMDAR -but not AMPAR- expression is present. In line, while NMDA-mediated effects (namely depression of the fEPSP slope) were significantly reduced in THY-Tau22 vs WT mice, no differences between genotypes could be observed following application of the AMPA receptor antagonist NBQX. Altogether, our data support that rather than directly impairing BDNF/TrkB expression as amyloid peptides do, Tau pathology induces alteration of NMDAR-dependent synaptic response to BDNF, possibly contributing to memory alterations. Fundings Ec FP7 MEMOSAD; ANR.