Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight. Objective: This study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-beta (A beta) and tau accumulation, and neuroinflammation in 5xFAD mice. Methods: Ten-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-beta (A beta), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2 alpha) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing. Results: 2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing A beta burden. Reduced levels of phosphorylated eIF2 alpha were also confirmed by immunofluorescence staining. Conclusions: These findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.