Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of Alzheimer’s disease

Abstract

Soluble amyloid-β-protein (Aβ) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aβ in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aβ. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aβ1–42. Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aβ-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aβ-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aβ which likely mediate the early stage of sporadic AD.

Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction

“…The most important element of ISR signaling is eIF2α phosphorylation and increased expression of ATF4. The increase in P-eIF2α and ATF4 has been observed in many neurodegenerative diseases (Oliveira and Lourenco, 2016 ; Zhu et al, 2019 ; Ghadge et al, 2020 ; Chang et al, 2022 ; Hu et al, 2022 ). Our results also showed that the same result occurs in POCD mice.…”

“…ATF4 then initiates a series of signaling cascades. Recent studies have suggested that ISR is involved in the pathogenesis of many neurodegenerative diseases (Chang et al, 2022 ), such as Alzheimer’s disease (Oliveira and Lourenco, 2016 ; Hu et al, 2022 ), amyotrophic lateral sclerosis (ALS; Ghadge et al, 2020 ), and Down syndrome (Zhu et al, 2019 ). It has been suggested that ISR had an important mechanistic connection with neurocognition (Pakos-Zebrucka et al, 2016 ), but the relationship between ISR and POCD is unclear.…”

Long-Term Depression-Inducing Low Frequency Stimulation Enhances p-Tau181 and p-Tau217 in an Age-Dependent Manner in Live Rats

“…1:1 DMSO and PEG400 in saline was used as vehicle control. The choice of dose and timing of ISRIB administration was based on previous reports [42] and our study of the pharmacokinetics of ISRIB in live rats [44]. Four (Supplementary Figure 1).…”

“…Increasing the ISR can facilitate mGluR-LTD [43,44] 104 while suppressing it has the opposite effect [43][44][45][46].…”

LTD-inducing low frequency stimulation enhances p-Tau181 and p-Tau217 in an age-dependent manner in live rats

“…Quantification of the protein expression was calculated with ImageJ (version 1.52a). The choice of dose and timing of ISRIB administration was based on previous reports (Krukowski et al, 2020) and our study of the pharmacokinetics of ISRIB in live rats (Hu et al, 2022). Four pair-housed relatively aged (17-18-month-old) rats received a single daily injection of ISRIB (2.5 mg/kg, i.p.)…”