Targeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder

Abstract

Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-d-aspartate receptor (NMDAR). Age-related cognitive disorders includes Alzheimer's disease (AD), vascular dementia (VD), and age-associated memory impairment (AAMI). Based on the critical role of NMDAR-dependent long-term potentiation (LTP) in memory, the increase of reactive oxygen species in cognitive disorders, and the sensitivity of NMDAR to the redox status, converging lines have suggested the redox-altered NMDAR-dependent plasticity might underlie the synaptic dysfunctions associated with cognitive disorders. In this review, we summarize the involvement of redox-altered plasticity in cognitive disorders by presenting the available evidence. According to reports from our laboratory and other groups, this "redox-altered plasticity" is more similar to functional changes rather than organic injuries, and strategies targeting redox-altered plasticity using pharmacological agents might reverse synaptic dysfunctions and memory abnormalities in the early stage of cognitive disorders. Targeting redox modifications for NMDARs may serve as a novel therapeutic strategy for memory deficits.

Keywords: AAMI, age-associated memory impairment; AD, Alzheimer's disease; AMPARs, α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors; CaMKII, Ca2+/calmodulin-dependent protein kinase II; Cognitive disorder; DG, dentate gyrus; DS, Down syndrome; DTNB, 5,5-dithio-bis-2-nitrobenzoic acid; DTT, dithiothreitol; EPSPs, excitatory postsynaptic potentials; GSK-3β, glycogen synthase kinase-3β; Glu, glutamate; H2O2, hydrogen peroxide; HFS, high-frequency stimulation; Hydrogen sulfide; LFS, low-frequency stimulation; LTD, long-term depression; LTP, long-term potentiation; Learning and memory; Long-term potentiation; MF, mossy fiber; N-Methyl-d-aspartate receptor; NAC, N-acetyl cysteine; NADPH, nicotinamide adenine dinucleotide phosphate; NMDARs, N-methyl-d-aspartate receptors; NO, nitric oxide; Oxidative stress; PTM, posttranslational modification; ROS, reactive oxygen species; Reactive oxygen species; SC, Schaffer collateral; SNOC, S-nitrosocysteine; Synaptic plasticity; TFAM, mitochondrial transcription factor A; VD, vascular dementia.