Kommaddi, Reddy PeeraTomar, Deepika SinghKarunakaran, SmithaBapat, DeeptiNanguneri, SiddharthRay, AjitSchneider, Bernard L.Nair, DeepakRavindranath, Vijayalakshmi2019-11-272019-11-272019-11-272019-12-2010.1089/ars.2019.7754https://infoscience.epfl.ch/handle/20.500.14299/163405WOS:000496636100001Aims: Reactive oxygen species (ROS) generated during Alzheimer's disease (AD) pathogenesis through multiple sources are implicated in synaptic pathology observed in the disease. We have previously shown F-actin disassembly in dendritic spines in early AD (34). The actin cytoskeleton can be oxidatively modified resulting in altered F-actin dynamics. Therefore, we investigated whether disruption of redox signaling could contribute to actin network disassembly and downstream effects in the amyloid precursor protein/presenilin-1 double transgenic (APP/PS1) mouse model of AD. Results: Synaptosomal preparations from 1-month-old APP/PS1 mice showed an increase in ROS levels, coupled with a decrease in the reduced form of F-actin and increase in glutathionylated synaptosomal actin. Furthermore, synaptic glutaredoxin 1 (Grx1) and thioredoxin levels were found to be lowered. Overexpressing Grx1 in the brains of these mice not only reversed F-actin loss seen in APP/PS1 mice but also restored memory recall after contextual fear conditioning. F-actin levels and F-actin nanoarchitecture in spines were also stabilized by Grx1 overexpression in APP/PS1 primary cortical neurons, indicating that glutathionylation of F-actin is a critical event in early pathogenesis of AD, which leads to spine loss. Innovation: Loss of thiol/disulfide oxidoreductases in the synapse along with increase in ROS can render F-actin nanoarchitecture susceptible to oxidative modifications in AD. Conclusions: Our findings provide novel evidence that altered redox signaling in the form of S-glutathionylation and reduced Grx1 levels can lead to synaptic dysfunction during AD pathogenesis by directly disrupting the F-actin nanoarchitecture in spines. Increasing Grx1 levels is a potential target for novel disease-modifying therapies for AD.Biochemistry & Molecular BiologyEndocrinology & Metabolismgrx1oxidationreactive oxygen speciesneurodegenerative diseasecytoskeletoncognitiondendritic spinescell-deaths-glutathionylationlipid-peroxidationprotein oxidationredox regulationstressbrainprogressionhomeostasistext::journal::journal article::research article