G-4437

Endoplasmic reticulum stress PERK-ATF6-CHOP pathways are involved in cognitive function deficits in Alzheimer's disease: The rescue effect of Sodium butyrate

 Mahan Safari ¹ ℗, Leila Chodari ² ©, Shadi Mohammadpour-Asl ³, Amin Alijani ¹, Shirin Abdollahi ¹, Maria Javadi ¹   

 
Abstract

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder recognized as the foremost cause of dementia, currently affecting more than 44 million individuals worldwide. Significant memory impairment, cognitive deficits, and various behavioral alterations, including psychosis, hallucinations, and reduced social engagement, characterize this condition. A significant factor involved in the development of Alzheimer's disease is stress in the endoplasmic reticulum (ER), which is crucial for both the onset and progression of neurodegenerative disease. The accumulation of misfolded proteins within the ER lumen impairs its function, initiating unfolded protein response (UPR) pathways such as PERK, IRE-1A, and ATF-6 in an effort to restore normalcy. If these corrective measures fail, it can lead to cell death through the increased expression of pro-apoptotic proteins like CHOP, caspase-12, and caspase-8. The prefrontal cortex (PFC), essential for cognitive abilities like attention and long-term memory due to its connections with subcortical regions, is impacted in AD, resulting in symptoms such as delusions and depression. Sodium butyrate (NaB), a salt of short-chain fatty acid, easily crosses the blood-brain barrier and shows neuroprotective properties by regulating neuroinflammation and the release of neurotransmitters. This research aims to examine the effects of NaB on ERS markers in the PFC of a rat model of AD. Methods and Materials: Male Wistar rats were divided into three groups (n=8): sham (Sham), AD-induced (STZ), and AD + NaB (STZ + NaB). AD was induced by bilateral intracerebroventricular injection of streptozotocin (3 mg/kg). NaB (400 mg/kg, i.p.) was administered daily for 30 days. PFC tissue was analyzed for protein levels of ATF6, CHOP, p-PERK, PERK, cleaved caspase-12, and cleaved caspase-8 using western immunoblotting. Amyloid plaque density was measured using Thioflavin S staining. Cognitive functions were assessed via the Morris water maze test. Data were analyzed with one-way ANOVA followed by Tukey's post-hoc test (p0.05 considered significant). Results: According to the results, the STZ group showed significantly increased ATF6, CHOP, p-PERK/PERK ratio, cleaved caspase-12, and cleaved caspase-8 levels in PFC, with increased levels of density of amyloid plaques (p0.001) compared to the Sham group. NaB treatment reversed these changes: reduced ATF6 (p0.01), CHOP(p0.001), p-PERK/PERK (p0.01), cleaved caspase-12 (p0.001), cleaved caspase-8 (p0.001), and improved cognitive performance compared to STZ. Conclusion and Discussion: It seems NaB attenuates PFC damage in AD model rats by suppressing ERS, promoting adaptive ER stress, and improving protein folding, potentially via ATF6, CHOP, p-PERK/PERK pathway modulation to reduce apoptosis. These findings suggest NaB as a promising therapeutic for AD cognitive deficits, warranting further clinical exploration.

Keywords: Alzheimer’s disease, cognitive function, Sodium butyrate, Endoplasmic reticulum stress, Prefrontal