Up-regulation of the IL-1 signaling pathway enhances gene expression of transcription factors (Jun, Junb, Jund, Fos, and Fosb)
DOI:
https://doi.org/10.61173/9fk4yy06Keywords:
Alzheimer‘s disease, IL-1 signaling pathway, microglia, IL-1 R2, expression of Bace-1Abstract
This paper focuses on the experiment method to find out the relationship between the IL-1 signaling pathway and the transcription factors; we use 5xFAD mice with targeted deletion of Bace-1 in microglia,We conjecture that the up-regulation of the IL-1 signaling pathway enhances gene expression of transcription factors (Jun, Junb, Jund, Fos, and Fosb), which probably increases the transition microglial signature. The specifically targeted inhibition of BACE-1 in microglia will likely offer a superior therapeutic alternative for improving AD outcomes, circumventing the safety concerns associated with neuronal deletion or global inhibition of BACE-1.
References
microglia within homeostatic, DAM-1, DAM- Related Dementias Summit 2016: National Research Priorities.” 2, transition states Neurology, U.S. National Library of Medicine, pubmed.ncbi.
nlm.nih.gov/29117955/. Accessed 16 Aug. 2023. 2. Cai, Huaibin, 7. IMPLICATION et al.“ BACE1 Is the Major β-Secretase for Generation of AΒ If the outcome of experiment 3 deviates from our initial Peptides by Neurons.” Nature News, Nature Publishing Group, expectations, it suggests a lack of correlation between www.nature.com/articles/nn0301_233. Accessed 16 Aug. 2023. the IL-1 signaling pathway and TF expression. Perhaps 3. Roberds SL Anderson J Basi G Bienkowski MJ Branstetter the C-terminal fragment (CTF) produced by cleavage of DG Chen KS Freedman SB Frigon NL Games D Hu K Johnson- IL-1R2 inside the cell shields some signal transduction Wood K Kappenman KE Kawabe TT Kola I Kuehn R Lee M and enhances TF activity. The cleavage of IL-1R2 may Liu W Motter R Nichols NF Power M Robertson DW Schenk possibly generate an intracellular C-terminal fragment D Schoor M Shopp GM Shuck ME Sinha S Sven. “BACE (CTF) that may shield certain signal transduction Knockout Mice Are Healthy despite Lacking the Primary Betapathways and enhance the activity of transcription factors Secretase Activity in Brain: Implications for Alzheimer’s Disease (TFs). Deletion of Bace-1 leads to reduced cleavage of IL- Therapeutics.” Human Molecular Genetics, U.S. National 1R2, resulting in decreased CTF levels in microglia cells. Library of Medicine, pubmed.ncbi.nlm.nih.gov/11406613/. Transcription factor activity is enhanced without CTF Accessed 17 Aug. 2023. shielding, leading to increased DAM-1 production. 4. M , Imbimbo BP Watling. “Investigational BACE Inhibitors If BACE-1 also cleaves IL-1R1, the upregulation of for the Treatment of Alzheimer’s Disease.” Expert Opinion BACE-1 will decrease IL-1R1 expression, thereby on Investigational Drugs, U.S. National Library of Medicine, inhibiting the IL-1 signaling pathway. pubmed.ncbi.nlm.nih.gov/31661331/. Accessed 17 Aug. 2023. If the observed outcomes are consistent with our 5. Singh N Benoit MR Zhou J Das B Davila-Velderrain J Kellis expectations, the implication of this finding is still yet to M Tsai LH Hu X Yan R “BACE-1 Inhibition Facilitates the be determined through further experiments on mouse and Transition from Homeostatic Microglia to Dam-1.” Science clinical trials. Future medicine research could prioritize Advances, U.S. National Library of Medicine, pubmed.ncbi.nlm. targeting BACE-1 or IL-1R2 in microglia or IL-1 nih.gov/35714196/.Accessed 17 Aug.2023. signaling. Future research could focus on investigating the 6. Kuhn, Peer-Hendrik, et al. “Regulated Intramembrane intricate mechanism underlying the impact of TF genes Proteolysis of the Interleukin-1 Receptor II by α-,β-,and on microglia in relation to DAM-1, with the ultimate goal γ-Secretase.”www.jbc.org/article/S0021-9258(19)58180-7/ of developing potential pharmacological interventions for fulltext. Accessed 18 Aug.2023 modulating the levels of DAM-1 or DAM-2. 7. Peters, Vanessa A., et al. “IL-1 Receptor 2 (IL-1R2) and Its Role in Immune Regulation.” Brain, Behavior, and Immunity, 8. CONCLUSION U.S. National Library of Medicine, Aug. 2013, www.ncbi.nlm. This paper has argued that targeted deletion of Bace-1 nih.gov/pmc/articles/PMC3610842/.Accessed 18 Aug.2023 in mice decreases the concentration of sIL-1 R2 outside 8. Singh N Das B Zhou J Hu X Yan R “Targeted BACE- the microglia, enhancing the IL-1 signaling pathway, 1 Inhibition in Microglia Enhances Amyloid Clearance which induces expression of transcription factors such as and Improved Cognitive Performance.” Science Advances, Jun, Junb, Jund, Fos, and Fosb in the transition signature U.S. National Library of Medicine, pubmed.ncbi.nlm.nih. transition, thus more microglia transit from homeostatic gov/35857844/. Accessed 18 Aug.2023
Downloads
Published
Issue
Section
License
Copyright (c) 2024 by the authors.
This work is licensed under a Creative Commons Attribution 4.0 International License.
