Just like a delicate balancing act, the brain of individuals with Alzheimer’s disease (AD) struggles to maintain order. The misfolded proteins, Amyloid β and Tau, disrupt the normal functioning of cells, signaling an imbalance in the endoplasmic reticulum (ER) proteostasis. This triggers a response known as the unfolded protein response (UPR), consisting of two pathways: the adaptive UPR and the apoptotic UPR. The former attempts to restore balance by reducing protein production, promoting proper protein folding with the help of chaperones, eliminating misfolded proteins through degradation, and limiting ribosomal translation. Conversely, if the stress is too severe, the apoptotic UPR is activated, leading to cell death. Another player in this complex puzzle is microRNAs (miRNAs), which play a role in regulating gene expression. Dysregulated miRNAs have been linked to various diseases, including AD. Although studies have hinted at a connection between ERUPR signaling and miRNA dysregulation, more research is needed to uncover the full picture. This review gathers insights from original research and review articles to shed light on the interplay between ER stress, UPR signaling, and miRNA dysregulation in the pathogenesis of AD.
Alzheimer’s disease (AD) is a neurodegenerative proteinopathic disease. The deposits of misfolded Amyloid β and Tau proteins in the brain of patients with AD suggest an imbalance in endoplasmic reticulum (ER) proteostasis. ER stress is due to accumulation of aberrant proteins in the ER lumen, which then leads to activation of three sensor protein pathways that ultimately evokes the adaptive mechanism of the unfolded protein response (UPR). The UPR mechanism operates via adaptive UPR and the apoptotic UPR. Adaptive UPR tries to restore imbalance in ER hemostasis by decreasing protein production, enhanced chaperone involvement to restore protein folding, misfolded protein decay by proteasome, and suppression of ribosomal translation ultimately relieving the excessive protein load in the ER. Subsequently, apoptotic UPR activated under severe ER stress conditions triggers cell death. MicroRNAs (miRNAs) are small non-coding protein causing dysregulated translational of mRNAs in a sequential manner. They are considered to be critical elements in the maintenance of numerous cellular activities, hemostasis, and developmental processes. Therefore, upregulation or downregulation of miRNA expression is implicated in several pathogenic processes. Evidence from scientific studies suggest a strong correlation between ERUPR signaling and miRNA dysregulation but the research done is still dormant. In this review, we summarized the cross-talk between ER stress, and the UPR signaling processes and their role in AD pathology by scrutinizing and collecting information from original research and review articles.
Dr. David Lowemann, M.Sc, Ph.D., is a co-founder of the Institute for the Future of Human Potential, where he leads the charge in pioneering Self-Enhancement Science for the Success of Society. With a keen interest in exploring the untapped potential of the human mind, Dr. Lowemann has dedicated his career to pushing the boundaries of human capabilities and understanding.
Armed with a Master of Science degree and a Ph.D. in his field, Dr. Lowemann has consistently been at the forefront of research and innovation, delving into ways to optimize human performance, cognition, and overall well-being. His work at the Institute revolves around a profound commitment to harnessing cutting-edge science and technology to help individuals lead more fulfilling and intelligent lives.
Dr. Lowemann’s influence extends to the educational platform BetterSmarter.me, where he shares his insights, findings, and personal development strategies with a broader audience. His ongoing mission is shaping the way we perceive and leverage the vast capacities of the human mind, offering invaluable contributions to society’s overall success and collective well-being.