Abstract
MicroRNAs have been recognized as important regulators of the aging process. Trehalose, a natural disaccharide, displays protective effects against neuronal impairment through several mechanisms. However, little is known about the interactive effects of aging and trehalose on behavioral function and underlying miRNA expression patterns in the hippocampus of young and old rats. Male Wistar rats were divided into four groups. Two groups of aged (24 months) and young (4 months) rats were administered 2% trehalose solution for 30 days. Two other groups of aged and young rats received regular tap water. At the end of treatment, rats were assessed for cognitive behavior using the Morris water maze test. The expression level of miR-181c and mir-34c was also measured by qRT-PCR. We found that trehalose treatment reduced learning and memory impairment in old rats compared to control old animals (p < 0.05). In contrast, cognitive performance was not significantly improved in trehalose-treated young rats in comparison with young controls (p > 0.05). We also showed that the expression level of miR-181c was significantly increased in trehalose-treated rats (p < 0.01). However, analysis of miR-34c expression level indicated no significant difference between trehalose-treated old rats and non-treated old animals (p > 0.05). Our results indicated that trehalose treatment improved learning and memory function in aged rats by targeting miR-181c. Therefore, trehalose administration may provide a therapeutic strategy to ameliorate age-associated cognitive impairment.
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Abbreviations
- Mir:
-
MicroRNA
- AD:
-
Alzheimer’s disease
- PD:
-
Parkinson’s disease
References
Cole JH, Marioni RE, Harris SE, Deary IJ (2019) Brain age and other bodily ‘ages’: implications for neuropsychiatry. Mol Psychiatry 24:266–281
Persengiev SP, Kondova II, Bontrop RE (2012) The impact of MicroRNAs on brain aging and neurodegeneration. Curr gerontol geriatr res 2012:359369
Kinser HE, Pincus Z (2020) MicroRNAs as modulators of longevity and the aging process. Hum Genet 139:291–308
Sun Z-Z, Lv Z-Y, Tian W-J, Yang Y (2017) MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation–induced apoptosis. Int J Immunopathol Pharmacol 30:253–263
Li C, Liu Y, Liu D, Jiang H, Pan F (2016) Dynamic alterations of miR-34c expression in the hypothalamus of male rats after early adolescent traumatic stress. Neural Plast 1:8
Gullett JM, Chen Z, O’Shea A, Akbar M, Bian J, Rani A, Porges EC, Foster TC, Woods AJ, Modave F (2020) MicroRNA predicts cognitive performance in healthy older adults. Neurobiol Aging 95:186–194
Rani A, Barter J, Kumar A, Stortz JA, Hollen M, Nacionales D, Moldawer LL, Efron PA, Foster TC (2022) Influence of age and sex on microRNA response and recovery in the hippocampus following sepsis. Aging (Albany NY) 14:728
Olivieri F, Procopio AD, Montgomery RR (2014) Effect of aging on microRNAs and regulation of pathogen recognition receptors. Curr Opin Immunol 29:29–37
Mohammed CPD, Park JS, Nam HG, Kim K (2017) MicroRNAs in brain aging. Mech Ageing Dev 168:3–9
Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, Rao P, Farinelli L, Delalle I, Schmitt A, Falkai P (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308
Fang C, Li Q, Min G, Liu M, Cui J, Sun J, Li L (2017) MicroRNA-181c ameliorates cognitive impairment induced by chronic cerebral hypoperfusion in rats. Mol Neurobiol 54:8370–8385
Geekiyanage H, Chan C (2011) MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer’s disease. J Neurosci 31:14820–14830
Bourassa MW, Ratan RR (2014) The interplay between microRNAs and histone deacetylases in neurological diseases. Neurochem Int 77:33–39
Schonrock N, Humphreys DT, Preiss T, Götz J (2012) Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-β. J Mol Neurosci 46:324–335
Zhou H, Zhang R, Lu K, Yu W, Xie B, Cui D, Jiang L, Zhang Q, Xu S (2016) Deregulation of miRNA-181c potentially contributes to the pathogenesis of AD by targeting collapsin response mediator protein 2 in mice. J Neurol Sci 367:3–10
Takousis P, Sadlon A, Schulz J, Wohlers I, Dobricic V, Middleton L, Lill CM, Perneczky R, Bertram L (2019) Differential expression of microRNAs in Alzheimer’s disease brain, blood, and cerebrospinal fluid. Alzheimers Dement 15:1468–1477
Kao Y-C, Wang I, Tsai K-J (2018) miRNA-34c overexpression causes dendritic loss and memory decline. Int J Mol Sci 19:2323
Khalifeh M, Barreto GE, Sahebkar A (2021) Therapeutic potential of trehalose in neurodegenerative diseases: the knowns and unknowns. Neural Regen Res 16:2026
Sun L, Zhao Q, Xiao Y, Liu X, Li Y, Zhang J, Pan J, Zhang Z (2020) Trehalose targets Nrf2 signal to alleviate d-galactose induced aging and improve behavioral ability. Biochem Biophys Res Commun 521:113–119
Pagliassotti MJ, Estrada AL, Hudson WM, Wei Y, Wang D, Seals DR, Zigler ML, LaRocca TJ (2017) Trehalose supplementation reduces hepatic endoplasmic reticulum stress and inflammatory signaling in old mice. J Nutr Biochem 45:15–23
Nazari-Robati M, Akbari M, Khaksari M, Mirzaee M (2019) Trehalose attenuates spinal cord injury through the regulation of oxidative stress, inflammation and GFAP expression in rats. J Spinal Cord Med 42:387–394
Mari E, Ricci C, Pieraccini S, Spinozzi F, Mariani P, Ortore MG (2020) Trehalose effect on the aggregation of model proteins into amyloid fibrils. Life 10:60
Liu Y, Wang J, Hsiung G-YR, Song W (2020) Trehalose inhibits Aβ generation and plaque formation in alzheimer’s disease. Mol Neurobiol 57:3150–3157
Portbury SD, Hare DJ, Sgambelloni C, Perronnes K, Portbury AJ, Finkelstein DI, Adlard PA (2017) Trehalose improves cognition in the transgenic Tg2576 mouse model of Alzheimer’s disease. J Alzheimers Dis 60:549–560
Saffarpour S, Shaabani M, Naghdi N, Farahmandfar M, Janzadeh A, Nasirinezhad F (2017) In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain. Physiol Behav 175:97–103
Rajizadeh MA, Afarinesh MR, Zarif M, Mirasadi A, Esmaeilpour K (2019) Does caffeine therapy improve cognitive impairments in valproic acid rat model of autism? Toxin Reviews 40(4):654–664
Afgar A, Fard-Esfahani P, Mehrtash A, Azadmanesh K, Khodarahmi F, Ghadir M, Teimoori-Toolabi L (2016) MiR-339 and especially miR-766 reactivate the expression of tumor suppressor genes in colorectal cancer cell lines through DNA methyltransferase 3B gene inhibition. Cancer Biol Ther 17:1126–1138
Belviranli M, Okudan N (2018) Exercise training protects against aging-induced cognitive dysfunction via activation of the hippocampal PGC-1alpha/FNDC5/BDNF pathway. Neuromolecular Med 20:386–400
Wang G-W, Cao J, Wang X-Q (2019) Effects of ethanol extract from Bidens pilosa L. on spontaneous activity, learning and memory in aged rats. Exp gerontol 125:110651
Zhang W-L, Chi Y-L, Wang L-Z, Liu H, Zhao L-X, Su F (2018) Administrations of preoperative Shenmai injection and postoperative Shenfu injection, two ginseng containing TCM formulas, improve cognitive dysfunction in aged rats. Am J Chin Med 46:1065–1078
Gallagher M, Burwell R, Burchinal M (2015) Severity of spatial learning impairment in aging: development of a learning index for performance in the morris water maze. Behav Neurosci 129:540–548
Gocmez SS, Gacar N, Utkan T, Gacar G, Scarpace PJ, Tumer N (2016) Protective effects of resveratrol on aging-induced cognitive impairment in rats. Neurobiol Learn Mem 131:131–136
Ruan B, Wang R, Yang Y-J, Wang D-F, Wang J-W, Zhang C-C, Yuan D, Zhou Z-Y, Wang T (2019) Improved effects of saponins from panax japonicus on decline of cognitive function in natural aging rats via NLRP3 inflammasome pathway. Zhongguo Zhong yao za zhi Zhongguo zhongyao zazhi China journal of Chinese materia medica 44:344–349
He Q, Koprich JB, Wang Y, Yu W-b, Xiao B-g, Brotchie JM, Wang J (2016) Treatment with trehalose prevents behavioral and neurochemical deficits produced in an AAV α-synuclein rat model of Parkinson’s disease. Mol Neurobiol 53:2258–2268
Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of huntington disease. Nat med 10(2):148–154
Khalifeh M, Read MI, Barreto GE, Sahebkar A (2020) Trehalose against Alzheimer’s disease: insights into a potential therapy. BioEssays 42:1900195
Lee H-J, Yoon Y-S, Lee S-J (2018) Mechanism of neuroprotection by trehalose: controversy surrounding autophagy induction. Cell Death Dis 9:1–12
Indrieri A, Carrella S, Carotenuto P, Banfi S, Franco B (2020) The pervasive role of the miR-181 family in development, neurodegeneration, and cancer. Int J Mol Sci 21:2092
Hébert SS, Horré K, Nicolaï L, Bergmans B, Papadopoulou AS, Delacourte A, De Strooper B (2009) MicroRNA regulation of Alzheimer’s amyloid precursor protein expression. Neurobiol Dis 33:422–428
Schonrock N, Ke YD, Humphreys D, Staufenbiel M, Ittner LM, Preiss T, Götz J (2010) Neuronal microRNA deregulation in response to Alzheimer’s disease amyloid-β. PLoS ONE 5:e11070
Manzano-Crespo M, Atienza M, Cantero JL (2019) Lower serum expression of miR-181c-5p is associated with increased plasma levels of amyloid-beta 1–40 and cerebral vulnerability in normal aging. Transl neurodegener 8:1–10
Acknowledgements
Funding for this study was provided by Kerman University of Medical Sciences (Grant No. 99000089). We would like to express our gratitude to faculty members of Neuroscience Research Center of Kerman University of Medical Sciences.
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This work was supported by Kerman University of Medical Sciences (Grant No: 99000089).
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Conceptualization and funding acquisition: M.N.; Methodology design and supervision: M.N., M.S, A.A; Investigation and analysis: B.S., M.R.; Writing original draft: B.S. All authors reviewed the manuscript.
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This animal study was approved by the Institutional Animal Care and Use Committee of Kerman University of Medical Sciences (IR.KMU.REC.1399.350).
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Shafiei, B., Shabani, M., Afgar, A. et al. Trehalose Attenuates Learning and Memory Impairments in Aged Rats via Overexpression of miR-181c. Neurochem Res 47, 3309–3317 (2022). https://doi.org/10.1007/s11064-022-03687-w
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DOI: https://doi.org/10.1007/s11064-022-03687-w