Endoplasmic reticulum stress induces spatial memory deficits by activating GSK-3

Area of Science:

• Neuroscience
• Cellular Biology
• Pathology

Background:

• Endoplasmic reticulum (ER) stress is implicated in Alzheimer's disease (AD) pathogenesis.
• The precise molecular mechanisms linking ER stress to AD-related cognitive decline remain incompletely elucidated.
• The unfolded protein response (UPR) is a key cellular pathway activated by ER stress.

Purpose of the Study:

• To investigate the role of ER stress and the UPR in inducing spatial memory deficits and synaptic dysfunction.
• To elucidate the molecular pathway, specifically involving GSK-3β and CREB, through which ER stress impacts cognitive function.
• To assess the therapeutic potential of targeting GSK-3β in mitigating ER stress-induced memory impairments.

Main Methods:

• Induction of ER stress and UPR in Sprague-Dawley rats via intracerebroventricular injection of tunicamycin (TM).
• Assessment of UPR activation by measuring phosphorylation of key UPR sensors: PERK, IRE-1, and ATF-6.
• Evaluation of spatial memory function using behavioral tests.
• Analysis of synaptic plasticity markers and protein phosphorylation, including GSK-3β and CREB (pS129-CREB).
• Pharmacological inhibition of GSK-3β using SB216763 (SB) administered via hippocampal infusion.

Main Results:

• Tunicamycin treatment successfully induced UPR, evidenced by increased phosphorylation of PERK, IRE-1, and ATF-6.
• UPR activation led to significant spatial memory deficits and impaired synaptic plasticity in rats.
• TM treatment resulted in GSK-3β activation and increased phosphorylation of CREB at Ser129 (pS129-CREB), with nuclear co-localization of pY126-GSK-3β and pS129-CREB.
• Simultaneous inhibition of GSK-3β with SB216763 attenuated TM-induced UPR, ameliorated spatial memory impairments, and restored pS129-CREB levels and synaptic plasticity.

Conclusions:

• ER stress-induced UPR contributes to Alzheimer's disease-like spatial memory deficits.
• The GSK-3β/pS129-CREB signaling pathway is a critical mediator of ER stress-induced cognitive impairment.
• Targeting GSK-3β may represent a viable therapeutic strategy for managing ER stress-related neurological disorders such as AD.