Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression

摘要: Hyperexcitability of the hippocampus is a commonly observed phenomenon in years preceding diagnosis Alzheimer's disease (AD). Our previous work suggests dysregulation glutamate neurotransmission may mediate this hyperexcitability, and correlates with cognitive deficits rTg(TauP301L)4510 mouse model AD. To determine whether improving regulation would attenuate AD-related pathology, TauP301L mice were treated riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular levels. Riluzole-treated exhibited improved performance water radial arm maze Morris maze, associated decrease release increase uptake dentate gyrus, cornu ammonis 3 (CA3), 1 (CA1) regions hippocampus. Riluzole also attenuated TauP301L-mediated hippocampal vesicular transporter 1, which packages into vesicles influences release; major responsible removing from space. The reduction PSD-95 expression, marker excitatory synapses hippocampus, was rescued by riluzole. treatment reduced total levels tau, as well pathological phosphorylation conformational changes tau P301L mutation. These findings open new opportunities development clinically applicable therapeutic approaches to regulate vulnerable circuits those at risk