ISRIB prevents synaptic plasticity disruption and cognitive deficits in live rat model of Alzheimer's disease
BackgroundGrowing evidence shows that targeting the integrated stress response (ISR) through the inhibition of phosphorylation of eIF2α provides beneficial effects in animal models of neurodegenerative diseases including Alzheimer's disease (AD). However, those results are inconsistent and somehow conflicting likely due to the important role of ISR in both cell death and survival. Aβ-triggered pathologies including microvascular hypoxia, neuronal hyperactivation, neuroinflammation are common
... ation are common inducers of the ISR. The small-molecule inhibitor of the ISR called ISRIB, which only partially restores protein synthesis and confers neuroprotection without adverse effects on the pancreas most probably due to its state-dependent action, remarkably enhances cognition in animals.MethodsTo elucidate the roles of ISR in AD pathogenesis, we systemically treated exogenous Aβ-injected animals with ISRIB. Both Aβ-facilitated long-term depression (LTD) and Morris water maze were used to characterize Aβ-induced dysfunction. ResultsAcute treatment with ISRIB prevented Aβ-facilitated LTD and repeated treatment abrogated the spatial learning and memory deficits in exogenous Aβ-injected animals. Moreover, ISRIB restored aberrant high level of ATF4 to normal but did not affect the aberrant high level of phosphorylated eIF2α in the hippocampus of exogenous Aβ-injected rats. ConclusionsTargeting the ISR by suppressing the eIF2α cascade with ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD.