Modulating effect of liposomal miR-101 on the processes of amyloidogenesis, smell, sleep and neuroinflammation in experimental Alzheimer's disease
The current therapy for Alzheimer's disease does not give patients a chance of recovery. Therefore, it is relevant to study the novel factors of influence, in particular microRNA, on the pathogenic mechanisms of amyloidosis. The aim of this work was to determine the effect of miR-101 on early predictors of amyloidosis in experimental Alzheimer's disease in animals. The study was carried out on 25 male rats of 14 months of age. A model of Alzheimer's disease was created by intrahippocampal administration of Aβ40 aggregates to animals. Ten days later, a 10-day course of nasal administration of miR-101 in liposomes was launched. The level of endogenous Aβ42 and cytokines (TNFα, IL-6 and IL-10) was determined in the supernatants of the nerve tissues of the target brain structures (hippocampus, olfactory bulbs, and olfactory tubercles). A neuroethological method of presenting smells of isovaleric acid and peanut butter was used to assess the olfactory system functional state in the experimental rats. In the course of polygraphic registration of the sleep-wakefulness cycle, the representation of wakefulness and individual sleep phases, as well as proportion of incomplete and complete sleep cycles were determined. It was shown that injection of Aβ40 aggregates into the hippocampus simulates an amyloidogenic state in the rat’s hippocampus and olfactory tubercles, but not in the olfactory bulbs. Moreover, a pro-inflammatory state was registered in the hippocampus of the animal brain (an increase in the concentration of pro-inflammatory cytokines TNFα and IL-6), while the cytokine level in the olfactory bulbs and tubercles did not change. When studying the functional state of olfactory analyzers in the rats with Alzheimer's disease, we revealed negative changes in behavioral response to the smell of isovaleric acid and peanut butter. In terms of somnograms, the Aβ40 toxicity caused reduction in the deep slow-wave sleep stage combined with deficiency of the paradoxical sleep phase, and predominance of incomplete sleep cycles. Nasal therapy with miR-101 in liposomes normalized the level of Aβ42 in the hippocampus and olfactory tubercles and decreased the level of proinflammatory cytokines in the hippocampus. MiR-101 prevented olfactory disfunctions in assessing smells of isovaleric acid and peanut butter, increased the ratio of deep slow-wave sleep and paradoxical sleep in the cycle structure and restored proportion of complete sleep cycles in animals. Thus, liposomal miR-101 has an anti-amyloidogenic and anti-inflammatory effect in rats with a model of Alzheimer's disease. It helps to restore the functional state of olfactory analyzer and optimize structural organization of the sleep-wakefulness cycle in sick animals.
Berchenko O.G. (1982). Experimental study of the daily periodicity of emotional reactions and its changes in conditions of disturbed wakefulness-sleep processes. Thesis for the Degree of the Candidate of Biol. Sciences. Kharkov. 203 p.
Berchenko O.G. (1990). Neurophysiological organization of the wakefulness-sleep cycle in alcoholism of rats formed in different phases of emotional activity. Physiological Journal of the USSR, 76(6), 713–719.
Brai E., Alberi L. (2015). Simple and computer-assisted olfactory testing for mice. J. Vis. Exp., 100, e52944. https://doi.org/10.3791/52944
Brito L.M., Ribeiro-Dos-Santos Â., Vidal A.F. et al. (2020). Differential expression and miRNA-gene interactions in early and late mild cognitive impairment. Biology (Basel), 9(9), 251. https://doi.org/10.3390/biology9090251
Buresh J., Petran M., Zakhar I. (1962). Electrophysiological research methods. Moscow: Foreign Literature Publishing House. 466 p.
Dasgupta I., Chatterjee A. (2021). Recent advances in miRNA delivery systems. Methods Protoc., 4(1), 10. https://doi.org/10.3390/mps4010010
Drummond E., Wisniewski T. (2017). Alzheimer's disease: experimental models and reality. Acta Neuropathol., 133(2), 155-175. https://doi.org/10.1007/s00401-016-1662-x
Gao Y., Liu F., Fang L. et al. (2014). Genkwanin inhibits proinflammatory mediators mainly through the regulation of miR-101/MKP-1/MAPK pathway in LPS-activated macrophages. PLoS One, 9(5), e96741. https://doi.org/10.1371/journal.pone.0096741
Hammond S.M. (2015). An overview of microRNAs. Adv. Drug. Deliv. Rev., 87, 3–14. https://doi.org/10.1016/j.addr.2015.05.001
Hatfield S., Ruohola-Baker H. (2008). MicroRNA and stem cell function. Cell Tissue Res., 331(1), 57–66. https://doi.org/10.1007/s00441-007-0530-3
He L., Hannon G.J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet., 5, 522–531. https://doi.org/10.1038/nrg1379
Hebert S.S., Horre K., Nicolai L. et al. (2009). MicroRNA regulation of Alzheimer's Amyloid precursor protein expression. Neurobiol Dis., 33(3), 422–428. https://doi.org/10.1016/j.nbd.2008.11.009
Hoogland P., Van Den Berg R., Huisman E. (2003). Misrouted olfactory fibres and ectopic olfactory glomeruli in normal humans and in Parkinson and Alzheimer patients. Neuropathology and Applied Neurobiology, 29(3), 303–311. https://doi.org/10.1046/j.1365-2990.2003.00459.x
Huang Y., Shen X.J., Zou Q. et al. (2011). Biological functions of microRNAs: a review. J. Physiol. Biochem., 67(1), 129-139. https://doi.org/10.1007/s13105-010-0050-6
Iranifar E., Seresht B.M., Momeni F. et al. (2019). Exosomes and microRNAs: new potential therapeutic candidates in Alzheimer disease therapy. J. Cell Physiol., 234(3), 2296–2305. https://doi.org/10.1002/jcp.27214
Kassil V.G. (1993). Ontogenesis of the formation of various forms of higher nervous activity. Russian Journal of Physiology, 79(3), 1–26.
Kolobov V.V., Storozheva Z.I. (2014). Modern pharmacological models of Alzheimer's disease. Annals of Clinical and Experimental Neurology, 8(3), 38–44.
Kou X., Chen D., Chen N. (2020). The regulation of microRNAs in Alzheimer's disease. Front Neurol., 11, 288. https://doi.org/10.3389/fneur.2020.00288
Kovacs T. (2013). The olfactory system in Alzheimer’s disease: pathology, pathophysiology and pathway for therapy. Translational Neuroscience, 4(1), 34–45. https://doi.org/10.2478/s13380-013-0108-3
Kutter C., Svoboda P. (2008). Meeting report: miRNA, siRNA, piRNA. Knowns of the unknown. RNA Biology, 5(4), 181–188. https://doi.org/10.4161/rna.7227
Larson M., Semb H., Winblad B. et al. (1999). Odor identification in normal aging and early Alzheimer’s disease: effects of retrieval support. Neuropsychology, 13(1), 47–53. https://doi.org/10.1037//0894-418.104.22.168
Lobzin S.V., Sokolova M.G., Nalkin S.A. (2017). Influence of brain basal cholinergic system dysfunction on the condition of cognitive functions (literature rev.). North-Western State Med. University, 9(4), 53–58. https://doi.org/10.17816/mechnikov20179453-58
Long J.M., Lahiri D.K. (2011). MicroRNA-101 downregulates Alzheimer's amyloid-beta precursor protein levels in human cell cultures and is differentially expressed. Biochem. Biophys. Res. Commun., 404(4), 889–895. https://doi.org/10.1016/j.bbrc.2010.12.053
Lowry O., Rosebrough N., Farr A., Randall R. (1951). Protein measurement with Folin phenol reagent. J. Biol. Chem., 193(1), 265–275.
Ma T., Sun X., Sun S.et al. (2016). The study of peripheral blood miR-29a/101 in the diagnosis of Alzheimer's disease. Chin. J. Behav. Med. Brain Sci., 11, 1010–1014. https://doi.org/10.3760/cma.j.issn.1674-6554.2016.11.011
Madaeva I.M., Berdina O.N. (2017). Modern ideas of «slow sleep» and «ram sleep» and their role in pathogenesis of Alzheimer’s disease (review of literature). Acta Biomed. Sci., 2(4), 48–52. https://doi.org/10.12737/article_59fad513a63772.41901536
Manckoundia P., Putot A., Mahmoudi R. et al. (2016). Alterations in olfaction during Alzheimer disease, Parkinson disease and Lewy body disease. Journal of Alzheimer’s Disease & Parkinsonism, 6(5), 274. https://doi.org/10.4172/2161-0460.1000274
Manna I., De Benedittis S., Quattrone A. et al. (2020). Exosomal miRNAs as potential diagnostic biomarkers in Alzheimer's disease. Pharmaceuticals (Basel), 13(9), 243. https://doi.org/10.3390/ph13090243
Melnik S.A. (2007). Endocrine modification of the olfactory sensitivity of male mice. Abstract of the thesis for the Degree of the Candidate of Biol. Sciences. Nizhny Novgorod: UNN. 23 p.
Melnik S.A., Gladysheva O.S., Krylov V.N. (2012). Effect of preliminary exposure to isovaleric acid vapors on the olfactory sensitivity of male house mice. Sensory systems, 26(1), 52–56.
Mukhin V. (2013). Pathogenesis of the basalforebrain cholinergic dysfunction in Аlzheimer's disease. Sechenov Russian Physiological Journal, 99(7), 793–804.
Nag S., Tang F., Yee B.K. (2001). Chronic intracerebroventricular exposure to β-amyloid (1-40) impairs object recognition but does not affect spontaneous locomotor activity or sensorimotor gating in the rat. Exp. Brain Res.,136(1), 93–100. https://doi.org/10.1007/s002210000561
Pase P., Himali J.J., Grima N.A. et al. (2017). Sleep architecture and the risk of incident dementia in the community. Neurology, 89(12), 1244–1250. https://doi.org/10.1212/WNL.0000000000004373
Patel N., Hoang D., Miller N. et al. (2008). MicroRNAs can regulate human APP levels. Mol. Neurodegener., 3, 10. https://doi.org/10.1186/1750-1326-3-10
Pedroso de Lima M.C., Simões S., Pires P. et al. (2001). Cationic lipid-DNA complexes in gene delivery: From biophysics to biological applications. Adv. Drug Deliv. Rev., 47(2–3), 277–294. https://doi.org/10.1016/S0169-409X(01)00110-7
Saika R., Sakuma H., Noto D. et al. (2017). MicroRNA-101a regulates microglial morphology and inflammation. J. Neuroinflammation, 14, 109. https://doi.org/10.1186/s12974-017-0884-8
Silva M.V.F., Loures C.M.G., Alves L.C.V. et al. (2019). Alzheimer's disease: risk factors and potentially protective measures. J. Biomed. Sci., 26(1), 33. https://doi.org/10.1186/s12929-019-0524-y
Shulga S.M. (2014). Obtaining and characteristic of curcumin liposomal form. Biotechnol. Acta, 7(5), 55–61. https://doi.org/10.15407/biotech7.05.055
Silvestro S., Bramanti P., Mazzon E. (2019). Role of miRNAs in Alzheimer's disease and possible fields of application.Int. J. Mol. Sci., 20(16), 3979. https://doi.org/10.3390/ijms20163979
Sokolik V.V., Berchenko O.G., Shulga S.M. (2017). Comparative analysis of nasal therapy with soluble and liposomal forms of curcumin on rats with Alzheimer’s disease model. Journal of Alzheimer’s Disease & Parkinsonism, 7, 357. https://doi.org/10.4172/2161-0460.1000357
Sokolik V.V., Shulga S.M. (2015). Effect of curcumin liposomal form on angiotensin converting activity, cytokines and cognitive characteristics of the rats with Alzheimer’s disease model. Biotechnol. Acta, 8(6), 48–55. https://doi.org/10.15407/biotech8.06.048
Stepanichev M.Yu., Ivanov A.D., Lazareva N.A. (2016). Neurodegenerative changes caused by the introduction of a fragment (25-35) of β-amyloid peptide into the hippocampus are associated with the activation of NGF signaling. Bulletin of the Russian State Medical University, 1, 13–18. https://doi.org/10.24075/brsmu.2016-01-02
Wang C.C., Yuan J.R., Wang C.F. et al. (2016). Anti-inflammatory effects of Phyllanthus emblica L. on benzopyrene-induced precancerous lung lesion by regulating the IL-1β/miR-101/Lin28B signaling pathway. Integr. Cancer Ther., 16(4), 505–515. https://doi.org/10.1177/1534735416659358
Witt M., Galligan R.M., Despinoy J., Segal R. (2009). Olfactory behavioral testing in the adult mouse. J. Vis. Exp., 23, e949. https://doi.org/10.3791/949
Wu H.Z., Ong K.L., Seeher K. et al. (2016). Circulating microRNAs as biomarkers of Alzheimer's disease: Asystematic review. J. Alzheimers Dis., 49(3), 755–766. https://doi.org/10.3233/JAD-150619
Zhang Y., Wang Z., Gemeinhart R.A. (2013). Progress in microRNA delivery. J. Control. Release, 172(3), 962–974. https://doi.org/10.1016/j.jconrel.2013.09.015
Authors retain copyright of their work and grant the journal the right of its first publication under the terms of the Creative Commons Attribution License 4.0 International (CC BY 4.0), that allows others to share the work with an acknowledgement of the work's authorship.