The role of circulating free nucleic acids on Alzheimer's Disease
DOI:
https://doi.org/10.33448/rsd-v14i11.49915Keywords:
Alzheimer's disease, DAMPs, Neuroinflammation, Oxidative stress, Circulating free nucleic acids.Abstract
The study aims to understand the multifactorial foundation that could contribute to a deeper understanding of this issue. Alzheimer's disease is a neurodegenerative disorder primarily caused by idiopathic factors. However, it is almost universally agreed that genetic factors and the deposition of beta-amyloid plaques in senile plaques, along with tau protein, negatively influence its progression. Additionally, more recent evidence suggests a greater plausibility of factors that have been less discussed until now, such as circulating free nucleic acids. Oxidative stress caused by a neuroinflammatory process is triggered by the recognition of these substances in their circulating form, resulting from tissue damage caused by free radicals, which appear as damage-associated molecular patterns (DAMPs). This occurs through a positive feedback process involving the activation of the innate immune system, including microglia, astrocytes, blood-brain barrier proteins, cytokines, the complement system, and transmembrane receptors. In an insufficient attempt to clear the nervous system of DAMPs, this response ultimately induces and sustains a chronic immune cascade. However, despite the strong relationship between these factors and the development of Alzheimer's disease, the topic remains recent and clinically underexplored. Therefore, further theoretical exploration and the development of more laboratory tests are necessary to substantiate the theoretical framework discussed in the current literature on this subject.
References
Acta Neuropathologica, (2013); 126(4): 461-477. DOI: 10.1007/s00401-013-1182-x.
Burgos, K. et al. (2020). Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology. PLoS One, 2014; 9(5): e94839. DOI: 10.1371/journal.pone.0094839.
Cai, Z.; Hussain, M. D.; & Yan, L. J. (2014). Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. International Journal of Neuroscience. Informa Healthcare, , 2014.
Cisternas-García, L. et al. (2023). Cell-free RNA signatures predict Alzheimer’s disease. iScience, 2023; 26(12): 108534. DOI: 10.1016/j.isci.2023.108534.
Derkow, K. et al. (2018). Distinct expression of the neurotoxic microRNA family let-7 in the cerebrospinal fluid of patients with Alzheimer's disease. PLoS One, 2018; 13(7): e0200602. DOI: 10.1371/journal.pone.0200602.
Elkon, K. B. (2018). Review: Cell death, nucleic acids, and immunity: Inflammation beyond the grave. Arthritis & Rheumatology, 2018; 70(6): 805-816. DOI: 10.1002/art.40452.
Hanisch, U. K. (2002). Microglia as a source and target of cytokines. Glia, 2002; 40(2): 140-155. DOI: 10.1002/glia.10161.
Kenny, A. et al. (2019). Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer's disease. Scientific Reports, 2019; 9(1): 15437. DOI: 10.1038/s41598-019-51837-y.
Liu, C. G. et al. (2021). ABCA1-Labeled Exosomes in Serum Contain Higher MicroRNA-193b Levels in Alzheimer's Disease. Biomedical Research International, 2021; 2021: 5450397. DOI: 10.1155/2021/5450397.
Lin, Z. et al. (2021). Blood-brain barrier breakdown in relationship to Alzheimer and vascular disease. Annals of Neurology, 2021; 90(2): 227-238. DOI: 10.1002/ana.26134.
Li, H. et al. (2023). The role of signaling crosstalk of microglia in hippocampus on progression of ageing and Alzheimer's disease. Journal of Pharmaceutical Analysis, 2023; 13(7): 788-805. DOI: 10.1016/j.jpha.2023.05.008.
Li, Z. et al. (2024). Nuclear microRNA-mediated transcriptional control determines adult microglial homeostasis and brain function. Cell Reports, 2024; 43(3): 113964. DOI: 10.1016/j.celrep.2024.113964.
Lichtenstein, A. V.; Melkonyan, H. S.; Tomei, L. D.; & Umansky, S. R. (2001). Circulating nucleic acids and apoptosis. Annals of the New York Academy of Sciences, 2001; 945: 239-249. DOI: 10.1111/j.1749-6632.2001.tb03892.x.
Machado, A. P. R.; Carvalho, I. O.; Rocha & Sobrinho, H. M. da. (2020). Neuroinflamação na Doença de Alzheimer. Revista Brasileira Militar de Ciências, 2020; 6(14). DOI: 10.36414/rbmc.v6i14.33.
Mangalmurti, A.; & Lukens, J. R. (2022). How neurons die in Alzheimer's disease: implications for neuroinflammation. Current Opinion in Neurobiology, 2022; 75: 102575. DOI: 10.1016/j.conb.2022.102575.
Merlo, S.; Spampinato, S. F.; Caruso, G. I.; & Sortino, M. A. (2020). The ambiguous role of microglia in Aβ toxicity: chances for therapeutic intervention. Current Neuropharmacology, 2020; 18(5): 446-455. DOI: 10.2174/1570159X18666200131105418.
Murao, A. et al. (2021). Release mechanisms of major DAMPs. Apoptosis, 2021; 26(3-4): 152-162. DOI: 10.1007/s10495-021-01663-3.
Peña-Bautista, C. et al. (2019). Oxidative Damage of DNA as Early Marker of Alzheimer's Disease. International Journal of Molecular Sciences, 2019; 20(24): 6136. DOI: 10.3390/ijms20246136.
Prokop, S.; Miller, K. R.; & Heppner, F. L. (sd). Microglia actions in Alzheimer’s disease.
Roers, A.; Hiller, B.; & Hornung, V. (2016). Recognition of endogenous nucleic acids by the innate immune system. Immunity, 2016; 44(4): 739-754. DOI: 10.1016/j.immuni.2016.04.002.
Rossi, B.; Constantin, G.; & Zenaro, E. (2020). The emerging role of neutrophils in neurodegeneration. Immunobiology, 2020; 225(1): 151865. DOI: 10.1016/j.imbio.2019.10.014.
Sanders, O. D. (2023). Virus-like cytosolic and cell-free oxidatively damaged nucleic acids likely drive inflammation, synapse degeneration, and neuron death in Alzheimer's disease. Journal of Alzheimer's Disease Reports, 2023; 7(1): 1-19. DOI: 10.3233/ADR-220047.
Scheltens, P. et al. (2021). Alzheimer's disease. Lancet, 2021; 397(10284): 1577-1590. DOI: 10.1016/S0140-6736(20)32205-4.
Shah, A.; Kishore, U.; & Shastri, A. (2021). Complement system in Alzheimer's disease. International Journal of Molecular Sciences, 2021; 22(24): 13647. DOI: 10.3390/ijms222413647.
Tsuji, N.; & Agbor-Enoh, S. (2021). Cell-free DNA beyond a biomarker for rejection: Biological trigger of tissue injury and potential therapeutics. Journal of Heart and Lung Transplantation, 2021; 40(6): 405-413. DOI: 10.1016/j.healun.2021.03.007.
Van Den Berg, M. M. J. et al. (2020). Circulating microRNAs as potential biomarkers for psychiatric and neurodegenerative disorders. Progress in Neurobiology, 2020; 185: 101732. DOI: 10.1016/j.pneurobio.2019.101732.
Van Der Meer, A. J. et al. (2019). Systemic inflammation induces release of cell-free DNA from hematopoietic and parenchymal cells in mice and humans. Blood Advances, 2019; 3(5): 724-728. DOI: 10.1182/bloodadvances.2018018895.
Yang, J.; Wise, L.; & Fukuchi, K. I. (2020). TLR4 cross-talk with NLRP3 inflammasome and complement signaling pathways in Alzheimer's disease. Frontiers in Immunology, 2020; 11: 724. DOI: 10.3389/fimmu.2020.00724.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Lucas Locatelli Menegaz, David Cohen, Lucas Tiburski Sommer, Hadassa Lucena Sales Santos, Fernanda Cavinatto Pinto, Luiz Carlos Porcello Marrone, Maximiliano Isoppo Schaun, Cauan Tramontini Dias

This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.
