Exploring the Endoplasmic Reticulum's Role in Alzheimer's Disease and Its Potential as a Therapeutic Target

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive decline, particularly in memory and reasoning, which often culminates in severe dementia. Despite extensive research, the precise mechanisms underlying AD remain elusive. One of the key contributors to AD pathogenesis is the dysfunction of the endoplasmic reticulum (ER), an organelle involved in protein folding, calcium regulation, and lipid metabolism. When ER function is compromised, it leads to ER stress, a condition increasingly associated with AD development. ER stress activates the unfolded protein response (UPR), a cellular mechanism that, when overstressed, can result in neuronal death. Further research has revealed how ER stress interacts with other hallmark features of AD, including amyloid-beta (Aβ) plaque accumulation and tau hyperphosphorylation. Emerging evidence suggests that targeting ER stress and its associated pathways could present new therapeutic avenues for AD. This review examines the role of the ER in AD, outlining the mechanisms through which ER dysfunction accelerates disease progression and evaluating novel therapeutic strategies designed to restore ER balance and mitigate AD symptoms.

Keywords: Alzheimer's disease; amyloid‐beta; endoplasmic reticulum; unfolded protein response.