Abstract
Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by pathological hallmarks like β-amyloid peptide (Aβ) and clinical manifestations including cognitive impairment, psychiatry disorders, and behavioral changes. Salidroside (Sal) extracted from Rhodiola rosea L. showed protective effects against Aβ-induced neurotoxicity in a Drosophila AD model in our previous research. In the present study, daily doses of Sal were administered to APP/PS1 mice, a mouse model of AD, and several parameters were tested, including behavioral performance, Aβ status, levels of synapse-related proteins, and levels of PI3K/Akt targets of mTOR cell signaling pathway proteins. The behavioral testing showed an improvement in locomotor activity in the APP/PS1 mice after the administration of Sal. Treatment with Sal decreased both the soluble and insoluble Aβ levels and increased the expression of PSD95, NMDAR1, and calmodulin-dependent protein kinase II. The phosphatidylinositide PI3K/Akt/mTOR signaling was upregulated, which was in accordance with the above improvements from Sal treatment. Our findings suggested that Sal may protect the damaged synapses of the neurons in the APP/PS1 mice.
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References
Becker JT, Boller F, Lopez OL, Saxton J, McGonigle KL (1994) The natural history of Alzheimer's disease. Description of study cohort and accuracy of diagnosis. Arch Neurol 51(6):585–594
Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11(3):297–305
Chen T, Ma Z, Zhu L, Jiang W, Wei T, Zhou R, Luo F, Zhang K, Fu Q, Ma C, Yan T (2016) Suppressing receptor-interacting protein 140: a new sight for salidroside to treat cerebral ischemia. Mol Neurobiol 53(9):6240–6250. https://doi.org/10.1007/s12035-015-9521-7
Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puolivali J, Lesne S, Ashe KH, Muchowski PJ, Mucke L (2007) Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 282(33):23818–23828. https://doi.org/10.1074/jbc.M701078200
Chong ZZ, Shang YC, Wang S, Maiese K (2012) Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Prog Neurobiol 99(2):128–148. https://doi.org/10.1016/j.pneurobio.2012.08.001
De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV (2012) Alzheimer's disease. Sub-cellular Biochem 65:329–352. https://doi.org/10.1007/978-94-007-5416-4_14
Feng B, Raghavachari S, Lisman J (2011) Quantitative estimates of the cytoplasmic, PSD, and NMDAR-bound pools of CaMKII in dendritic spines. Brain Res 1419:46–52. https://doi.org/10.1016/j.brainres.2011.08.051
Gao J, He H, Jiang W, Chang X, Zhu L, Luo F, Zhou R, Ma C, Yan T (2015) Salidroside ameliorates cognitive impairment in a d-galactose-induced rat model of Alzheimer's disease. Behav Brain Res 293:27–33. https://doi.org/10.1016/j.bbr.2015.06.045
Gao J, Zhou R, You X, Luo F, He H, Chang X, Zhu L, Ding X, Yan T (2016) Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-kappaB pathway. Metab Brain Dis 31(4):771–778. https://doi.org/10.1007/s11011-016-9813-2
Grech-Baran M, Syklowska-Baranek K, Pietrosiuk A (2015) Biotechnological approaches to enhance salidroside, rosin and its derivatives production in selected Rhodiola spp. in vitro cultures. Phytochem Rev 14(4):657–674. https://doi.org/10.1007/s11101-014-9368-y
Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13(1):45–53
Jang SI, Pae HO, Choi BM, Oh GS, Jeong S, Lee HJ, Kim HY, Kang KJ, Yun YG, Kim YC, Chung HT (2003) Salidroside from Rhodiola sachalinensis protects neuronal PC12 cells against cytotoxicity induced by amyloid-beta. Immunopharmacol Immunotoxicol 25(3):295–304
Jin H, Pei L, Shu X, Yang X, Yan T, Wu Y, Wei N, Yan H, Wang S, Yao C, Liu D, Tian Q, Wang L, Lu Y (2016) Therapeutic intervention of learning and memory decays by salidroside stimulation of neurogenesis in aging. Mol Neurobiol 53(2):851–866. https://doi.org/10.1007/s12035-014-9045-6
Li QY, Wang HM, Wang ZQ, Ma JF, Ding JQ, Chen SD (2010) Salidroside attenuates hypoxia-induced abnormal processing of amyloid precursor protein by decreasing BACE1 expression in SH-SY5Y cells. Neurosci Lett 481(3):154–158. https://doi.org/10.1016/j.neulet.2010.06.076
Li Q, Wang J, Li Y, Xu X (2018) Neuroprotective effects of salidroside administration in a mouse model of Alzheimer's disease. Mol Med Rep 17(5):7287–7292. https://doi.org/10.3892/mmr.2018.8757
Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13(3):169–182. https://doi.org/10.1038/nrn3192
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2011) Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. J Pathol 225(1):54–62. https://doi.org/10.1002/path.2912
Liu Y, Yang X, Lei Q, Li Z, Hu J, Wen X, Wang H, Liu Z (2015) PEG-PEI/siROCK2 protects against Abeta42-induced neurotoxicity in primary neuron cells for Alzheimer disease. Cell Mol Neurobiol 35(6):841–848. https://doi.org/10.1007/s10571-015-0178-6
Ma T, Hoeffer CA, Capetillo-Zarate E, Yu F, Wong H, Lin MT, Tampellini D, Klann E, Blitzer RD, Gouras GK (2010) Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS ONE. https://doi.org/10.1371/journal.pone.0012845
Meilandt WJ, Cisse M, Ho K, Wu T, Esposito LA, Scearce-Levie K, Cheng IH, Yu GQ, Mucke L (2009) Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice. J Neurosci 29(7):1977–1986. https://doi.org/10.1523/JNEUROSCI.2984-08.2009
Murakoshi H, Yasuda R (2012) Postsynaptic signaling during plasticity of dendritic spines. Trends Neurosci 35(2):135–143. https://doi.org/10.1016/j.tins.2011.12.002
Nabavi SF, Braidy N, Orhan IE, Badiee A, Daglia M, Nabavi SM (2016) Rhodiola rosea L. and Alzheimer's disease: from farm to pharmacy. Phytotherapy Res: PTR 30(4):532–539. https://doi.org/10.1002/ptr.5569
Palmeri A, Mammana L, Tropea MR, Gulisano W, Puzzo D (2016) Salidroside, a bioactive compound of Rhodiola rosea, ameliorates memory and emotional behavior in adult mice. J Alzheimer's Dis: JAD 52(1):65–75. https://doi.org/10.3233/JAD-151159
Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M (2006) Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7(9):940–946. https://doi.org/10.1038/sj.embor.7400784
Ripoli C, Cocco S, Li Puma DD, Piacentini R, Mastrodonato A, Scala F, Puzzo D, D'Ascenzo M, Grassi C (2014) Intracellular accumulation of amyloid-beta (Abeta) protein plays a major role in Abeta-induced alterations of glutamatergic synaptic transmission and plasticity. J Neurosci 34(38):12893–12903. https://doi.org/10.1523/JNEUROSCI.1201-14.2014
Savioz A, Leuba G, Vallet PG (2014) A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease. Ageing Res Rev 18:86–94. https://doi.org/10.1016/j.arr.2014.09.004
Song X, Liu B, Cui L, Zhou B, Liu W, Xu F, Hayashi T, Hattori S, Ushiki-Kaku Y, Tashiro SI, Ikejima T (2017) Silibinin ameliorates anxiety/depression-like behaviors in amyloid beta-treated rats by upregulating BDNF/TrkB pathway and attenuating autophagy in hippocampus. Physiol Behav 179:487–493. https://doi.org/10.1016/j.physbeh.2017.07.023
Stefanova NA, Muraleva NA, Korbolina EE, Kiseleva E, Maksimova KY, Kolosova NG (2015) Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats. Oncotarget 6(3):1396–1413. https://doi.org/10.18632/oncotarget.2751
Sun H, Jia N, Guan L, Su Q, Wang D, Li H, Zhu Z (2013) Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring. Behav Brain Res 257:1–7. https://doi.org/10.1016/j.bbr.2013.08.044
Tiwari SK, Seth B, Agarwal S, Yadav A, Karmakar M, Gupta SK, Choubey V, Sharma A, Chaturvedi RK (2015) Ethosuximide induces hippocampal neurogenesis and reverses cognitive deficits in an amyloid-beta toxin-induced Alzheimer rat model via the phosphatidylinositol 3-kinase (PI3K)/Akt/Wnt/beta-catenin pathway. J Biol Chem 290(47):28540–28558. https://doi.org/10.1074/jbc.M115.652586
Tramutola A, Triplett JC, Di Domenico F, Niedowicz DM, Murphy MP, Coccia R, Perluigi M, Butterfield DA (2015) Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem 133(5):739–749. https://doi.org/10.1111/jnc.13037
Verma M, Beaulieu-Abdelahad D, Ait-Ghezala G, Li R, Crawford F, Mullan M, Paris D (2015) Chronic anatabine treatment reduces Alzheimer's disease (AD)-like pathology and improves socio-behavioral deficits in a transgenic mouse model of AD. PLoS ONE 10(5):e0128224. https://doi.org/10.1371/journal.pone.0128224
Wang M, Luo L, Yao L, Wang C, Jiang K, Liu X, Xu M, Shen N, Guo S, Sun C, Yang Y (2016) Salidroside improves glucose homeostasis in obese mice by repressing inflammation in white adipose tissues and improving leptin sensitivity in hypothalamus. Sci Rep 6:25399. https://doi.org/10.1038/srep25399
Wang C, Yu JT, Miao D, Wu ZC, Tan MS, Tan L (2014) Targeting the mTOR signaling network for Alzheimer's disease therapy. Mol Neurobiol 49(1):120–135. https://doi.org/10.1007/s12035-013-8505-8
Yu S, Liu M, Gu X, Ding F (2008) Neuroprotective effects of salidroside in the PC12 cell model exposed to hypoglycemia and serum limitation. Cell Mol Neurobiol 28(8):1067–1078. https://doi.org/10.1007/s10571-008-9284-z
Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G, Wang Z (2010) Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem Int 57(5):547–555. https://doi.org/10.1016/j.neuint.2010.06.021
Zhang J, Zhen YF, Pu Bu Ci R, Song LG, Kong WN, Shao TM, Li X, Chai XQ (2013) Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res 244:70–81. https://doi.org/10.1016/j.bbr.2013.01.037
Zhang B, Wang Y, Li H, Xiong R, Zhao Z, Chu X, Li Q, Sun S, Chen S (2016) Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer's disease models. Drug Des Dev Therapy 10:1335–1343. https://doi.org/10.2147/DDDT.S99958
Zhu L, Wei T, Gao J, Chang X, He H, Miao M, Yan T (2015) Salidroside attenuates lipopolysaccharide (LPS) induced serum cytokines and depressive-like behavior in mice. Neurosci Lett 606:1–6. https://doi.org/10.1016/j.neulet.2015.08.025
Zhu XN, Liu XD, Sun S, Zhuang H, Yang JY, Henkemeyer M, Xu NJ (2016) Ephrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour. Nature Commun 7:11096. https://doi.org/10.1038/ncomms11096
Funding
This work was supported by Grants from the Natural Science Fund of China (No. 91332107) and the Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-01-E00046).
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SC designed and supervised the whole study and involved in manuscript preparation. SS designed and supervised the study and was responsible for manuscript preparation and data analysis. HW was responsible for the acquisition, analysis of data for the work, and wrote the first draft of the manuscript. QL was involved in the data analysis and manuscript preparation.
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Wang, H., Li, Q., Sun, S. et al. Neuroprotective Effects of Salidroside in a Mouse Model of Alzheimer’s Disease. Cell Mol Neurobiol 40, 1133–1142 (2020). https://doi.org/10.1007/s10571-020-00801-w
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DOI: https://doi.org/10.1007/s10571-020-00801-w