MicroRNAs targeting Nicastrin regulate Aβ production and are affected by target site polymorphisms
Open accessAbstract
Despite the growing number of genome-wide association studies, the involvement of polymorphisms in microRNA target sites (polymiRTS) in Alzheimer's disease (AD) remains poorly investigated. Recently, we have shown that AD-associated single-nucleotide polymorphisms (SNPs) present in the 3' untranslated region (3'UTR) of amyloid precursor protein (APP) could directly affect miRNA function. In theory, loss of microRNA (miRNA) function could lead to risk for AD by increasing APP expression and Aβ peptide production. In this study, we tested the hypothesis that Nicastrin, a γ-secretase subunit involved in Aβ generation, could be regulated by miRNAs, and consequently affected by 3'UTR polymorphisms. Bioinformatic analysis identified 22 putative miRNA binding sites located in or near Nicastrin 3'UTR polymorphisms. From these miRNA candidates, six were previously shown to be expressed in human brain. We identified miR-24, miR-186, and miR-455 as regulators of Nicastrin expression, both in vitro and under physiological conditions in human cells, which resulted in altered Aβ secretion. Using luciferase-based assays, we further demonstrated that rs113810300 and rs141849450 SNPs affected miRNA-mediated repression of Nicastrin. Notably, rs141849450 completely abolished the miR-455-mediated repression of Nicastrin. Finally, the rs141849450 variant was identified in 1 out of 511 AD cases but not in 631 controls. These observations set the stage for future studies exploring the role of miRNAs and 3'UTR polymorphisms in AD.
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miR-186 represses Aβ generation at both β- and γ-cleavage steps.
“Recently, nicastrin, a subunit of γ-secretase complex, was identified as a target of miR-186 (Delay et al. 2014), suggesting that miR-186 represses Aβ generation at both β- and γ-cleavage steps.”
From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Delay et al. 2014
Nicastrin, a subunit of γ-secretase complex, is a target of miR-186.
“Recently, nicastrin, a subunit of γ-secretase complex, was identified as a target of miR-186 (Delay et al. 2014), suggesting that miR-186 represses Aβ generation at both β- and γ-cleavage steps.”
From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Delay et al. 2014
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Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
The functions of animal microRNAs
Ambros, V. (2004) · Nature · doi:10.1038/nature02871 · Cited by 10,728 · see citing works
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404 · see citing works
The microRNA.org resource: targets and expression
Betel, D., Wilson, M. T., Gabow, A. P., Marks, D. S., & Sander, C. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm995 · Cited by 2,490 · see citing works
Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex
De Strooper, B. (2003) · Neuron · doi:10.1016/s0896-6273(03)00205-8 · Cited by 965 · see citing works
Garcia, D. M., Baek, D., Shin, C., Bell, G. W., Grimson, A., & Bartel, D. P. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2115 · Cited by 859 · see citing works
MicroRNA function: Multiple mechanisms for a tiny RNA?: FIGURE 1.
PILLAI, R. S. (2005) · RNA · doi:10.1261/rna.2248605 · Cited by 681 · see citing works
Human polymorphism at microRNAs and microRNA target sites
Saunders, M. A., Liang, H., & Li, W. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611347104 · Cited by 654 · see citing works
Canadian study of health and aging: study methods and prevalence of dementia.
(1994) · Europe PMC (PubMed Central) · Cited by 613 · see citing works
Wang, G., van der Walt, J. M., Mayhew, G. M., Li, Y., Zuchner, S. L., Scott, W. K., Martin, E. R., & Vance, J. M. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.021 · Cited by 441 · see citing works
Natural selection on human microRNA binding sites inferred from SNP data
Chen, K., & Rajewsky, N. (2006) · Nature Genetics · doi:10.1038/ng1910 · Cited by 391 · see citing works
MicroRNAs in Alzheimer’s Disease
Wang, M., Qin, L., & Tang, B. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00153 · Cited by 307 · see citing works
Rademakers, R., Eriksen, J. L., Baker, M. C., Robinson, T., Ahmed, Z., Lincoln, S., Finch, N. A., Rutherford, N. J., Crook, R., Josephs, K. A., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn257 · Cited by 290 · see citing works
Yu, Z., Li, Z., Jolicoeur, N., Zhang, L., Fortin, Y., Wang, E., Wu, M., & Shen, S. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm480 · Cited by 259 · see citing works
Edbauer, D., Winkler, E., Haass, C., & Steiner, H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.132277899 · Cited by 224 · see citing works
MicroRNAs in Alzheimer's disease
Delay, C., Mandemakers, W., & Hébert, S. S. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.01.003 · Cited by 185 · see citing works
Self-citationHsiung, G. R. (2004) · Canadian Medical Association Journal · doi:10.1503/cmaj.1031789 · Cited by 164 · see citing works
Self-citationFeldman, H., Levy, A. R., Hsiung, G. R., Peters, K. R., Donald, A., Black, S. E., Bouchard, R. W., Gauthier, S. G., Guzman, D., Hogan, D. B., et al. (2003) · Neuroepidemiology · doi:10.1159/000071189 · Cited by 140 · see citing works
Self-citationAlzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function
Delay, C., Calon, F., Mathews, P. M., & Hébert, S. S. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-70 · Cited by 130 · see citing works
Self-citationHébert, S. S., Wang, W.-X., Zhu, Q., & Nelson, P. T. (2013) · Journal of Alzheimer's Disease · doi:10.3233/jad-122350 · Cited by 110 · see citing works
Self-citationNyabi, O., Bentahir, M., Horré, K., Herreman, A., Gottardi-Littell, N. R., Broeckhoven, C. V., Merchiers, P., Spittaels, K., Annaert, W. G., & Strooper, B. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306957200 · Cited by 110 · see citing works
Genetic Architecture of MicroRNA Expression: Implications for the Transcriptome and Complex Traits
Gamazon, E. R., Ziliak, D. M., Im, H. K., LaCroix, B. L., Park, D. S., Cox, N. J., & Huang, R. S. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.04.023 · Cited by 97 · see citing works
A genome-wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS
Richardson, K., Lai, C., Parnell, L. D., Lee, Y., & Ordovás, J. M. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-504 · Cited by 85 · see citing works
Inferring causative variants in microRNA target sites
Thomas, L. F., Saito, T., & Sætrom, P. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr414 · Cited by 70 · see citing works
Lupton, M. K., Proitsi, P., Danillidou, M., Tsolaki, M., Hamilton, G., Wroe, R., Pritchard, M., Lord, K., Martin, B. M., Kłoszewska, I., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017298 · Cited by 23 · see citing works
Nicastrin Overexpression in Transgenic Mice Induces Aberrant Behavior and APP Processing
Goo, J. S., Kim, Y. B., Shim, S. B., Jee, S. W., Lee, S. H., Kim, J. E., Hwang, I. S., Lee, Y. J., Kwak, M. H., Lim, C. J., et al. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8453-3 · Cited by 8 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
MicroRNAs in Alzheimer’s Disease
Wang, M., Qin, L., & Tang, B. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00153 · Cited by 307 · see citing works
miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo
Smith, P. Y., Hernandez-Rapp, J., Jolivette, F., Lecours, C., Bisht, K., Goupil, C., Dorval, V., Parsi, S., Morin, F., Planel, E., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv377 · Cited by 233 · see citing works
Self-citationNoncoding RNAs in Alzheimer's disease
Idda, M. L., Munk, R. B., Abdelmohsen, K., & Gorospe, M. (2018) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1463 · Cited by 206 · see citing works
Millan, M. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.03.004 · Cited by 146 · see citing works
microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases
Basak, I., Patil, K. S., Alves, G. W., Larsen, J. P., & Møller, S. G. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2093-x · Cited by 120 · see citing works
miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression
Kim, J., Yoon, H., Chung, D., Brown, J. L., Belmonte, K. C., & Kim, J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13507 · Cited by 102 · see citing works
“Recently, nicastrin, a subunit of c-secretase complex, was identified as a target of miR-186 (Delay et al. 2014), suggesting that miR-186 represses Ab generation at both b- and c-cleavage steps.”
BackgroundParsi, S., Smith, P. Y., Goupil, C., Dorval, V., & Hébert, S. S. (2015) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2015.33 · Cited by 89 · see citing works
Self-citationMicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms
Dehghani, R., Rahmani, F., & Rezaei, N. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0042 · Cited by 72 · see citing works
Wu, D., Wen, X., Wang, Y., Han, X., Wang, S., Shen, M., Fan, S., Zhuang, J., Zhang, Z.-F., Shan, Q., et al. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26843 · Cited by 28 · see citing works
RetractedEffects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice
Tian, T., Bai, D. G., Li, W., Huang, G., & Liu, H. (2016) · Nutrients · doi:10.3390/nu8090556 · Cited by 27 · see citing works
Versatile role of miR-24/24-1*/24-2* expression in cancer and other human diseases.
Mukherjee, S., Shelar, B., & Krishna, S. (2022) · PubMed Central · Cited by 26 · see citing works
Zhang, T., Shen, Y., Guo, Y., & Yao, J. (2021) · Aging · doi:10.18632/aging.203017 · Cited by 23 · see citing works
Tan, Z., Li, W., Cheng, X., Zhu, Q., & Zhang, X. (2022) · Biomolecules · doi:10.3390/biom13010018 · Cited by 24 · see citing works
The Potential Role of Dysregulated miRNAs in Alzheimer’s Disease Pathogenesis and Progression
Patel, A. A., Ganepola, G. A. P., Rutledge, J. R., & Chang, D. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181078 · Cited by 22 · see citing works
MicroRNAs Modulate the Pathogenesis of Alzheimer’s Disease: An In Silico Analysis in the Human Brain
Gugliandolo, A., Chiricosta, L., Boccardi, V., Mecocci, P., Bramanti, P., & Mazzon, E. (2020) · Genes · doi:10.3390/genes11090983 · Cited by 20 · see citing works
MicroRNA-Target Interaction Regulatory Network in Alzheimer’s Disease
Turk, A., Kunej, T., & Peterlin, B. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11121275 · Cited by 19 · see citing works
Maloney, B., Balaraman, Y., Liu, Y., Chopra, N., Edenberg, H. J., Kelsoe, J. R., Nürnberger, J. I., & Lahiri, D. K. (2019) · Scientific Reports · doi:10.1038/s41598-019-54076-3 · Cited by 17 · see citing works
Delay, C., Grenier‐Boley, B., Amouyel, P., Dumont, J., & Lambert, J. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0186-x · Cited by 15 · see citing works
Self-citationmiR‐186 in Alzheimer's disease: a big hope for a small RNA?
Halima, S. B., Siegel, G., & Rajendran, L. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13573 · Cited by 14 · see citing works
Secretases-related miRNAs in Alzheimer’s disease: new approach for biomarker discovery
Hajjari, S. N., Mehdizadeh, M., Sadigh‐Eteghad, S., Shanehbandi, D., Teimourian, S., & Baradaran, B. (2017) · Neurological Sciences · doi:10.1007/s10072-017-3086-3 · Cited by 13 · see citing works
Arif, S., Qazi, T. J., Quan, Z., Ni, J., Li, Z., Qiu, Y., & Qing, H. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102614 · Cited by 13 · see citing works
Piergiorge, R. M., Francisco, R. D. S., de Vasconcelos, A. T. R., & Santos-Rebouças, C. B. (2023) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2023.107494 · Cited by 6 · see citing works
Implication of microRNAs in Alzheimer's disease pathogenesis
Zoltowska, K. M., Laskowska-Kaszub, K., Nagaraj, S., & Wojda, U. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-815868-5.00009-8 · Cited by 6 · see citing works
Early detection of Alzheimer’s disease using small RNAs. Results from the EPAD cohort
Sikosek, T., Heuvelman, M., Mika, J., Kahraman, M., Jehn, J., Frank, M., Daniel-Moreno, A., Ceiler, J., Skottke, J., Sánchez-Delgado, M., et al. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100257 · Cited by 5 · see citing works
Lázaro, S. P., Martín‐Burriel, I., Cozzuto, L., Ponomarenko, J. V., Badiola, J. J., Bolea, R., & Toivonen, J. M. (2025) · Veterinary Research · doi:10.1186/s13567-025-01566-0 · Cited by 2 · see citing works
Rare Intronic Variations inTP73Gene Found in Patients with Alzheimer’sDisease
Bhaumik, P., Ghosh, P., Biswas, A., Ghosh, S., Pal, S., Sarkar, B., & Dey, S. K. (2017) · International Journal of Human Genetics · doi:10.1080/09723757.2017.1421438 · Cited by 2 · see citing works
The potential role of microRNA-155 in Neurodegenerative diseases with a focus on Alzheimer's diseasePreprint
Rasmi, Y., Shokati, A., Rahimi, A., Aziz, S. G., Farnamian, Y., Hassan, A., & Alipour, S. (2022) · Research Square · doi:10.21203/rs.3.rs-2314903/v1
The role of MicroRNAs in Alzheimer’s disease: from pathogenesis to therapeutic potential
Zhou, Y., Li, S., & Xiang, J. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-11746-6
- Authors
- Delay, C., Dorval, V., Fok, A., Grenier-Boley, B., Lambert, J.-C., Hsiung, G.-Y., & Hébert, S. S.
- Affiliations
- Inserm (FR)
- Université Laval (CA)
- University of British Columbia (CA)
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-07-18
- Volume
- 7
- Pages
- 67-67
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC4103510
- OpenAlex
- W1968783454
- Cited by
- 28
- References
- 26
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 4
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Alzheimer Society
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- microRNA, nicastrin, Alzheimer's disease, amyloid-beta production, 3' untranslated region, miR-24, miR-186, miR-455, gamma-secretase, APP, single nucleotide polymorphisms, microRNA regulation of gene expression
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