Ying-Hong Li: The First Affiliated Hospital of Shenzhen University (the Second People's Hospital of Shenzhen), Shenzhen, Guangdong Province, 518035, China. yinghongli@163.com.
Yu Jin: The First Affiliated Hospital of Shenzhen University (the Second People's Hospital of Shenzhen), Shenzhen, Guangdong Province, 518035, China.
Xu-Sheng Wang: The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, 518055, China.
Hong-Bo Chen: The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Beijing, 518055, China.
Ji Xu: The First Affiliated Hospital of Shenzhen University (the Second People's Hospital of Shenzhen), Shenzhen, Guangdong Province, 518035, China.
Li-Hong Duan: The First Affiliated Hospital of Shenzhen University (the Second People's Hospital of Shenzhen), Shenzhen, Guangdong Province, 518035, China.
Yu-Long Wang: The First Affiliated Hospital of Shenzhen University (the Second People's Hospital of Shenzhen), Shenzhen, Guangdong Province, 518035, China.
Xun Luo: Shenzhen Sanming Group, Spaulding Rehabilitation Hospital, Harvard Medical School, Charlestown, Boston, Massachusetts, 02129, USA.
Qing-Mei Wang: Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, Harvard Medical School, Charlestown, Boston, Massachusetts, 02129, USA.
Zheng-Zhi Wu: The First Affiliated Hospital of Shenzhen University (the Second People's Hospital of Shenzhen), Shenzhen, Guangdong Province, 518035, China.
OBJECTIVE: To evaluate the mechanisms underlying the protective effect of Chinese herbal medicine Fructus broussonetiae (FB) in both mouse and cell models of Alzheimer's disease (AD). METHODS: APP/PS1 mice treated with FB for 2 months and vehicle-treated controls were run through the Morris water maze and object recognition test to evaluate learning and memory capacity. RNA-Seq, Western blotting, and immunofluorescence staining were also conducted to evaluate the effects of FB treatment on various signaling pathways altered in APP/PS1 mice. To further explore the mechanisms underlying FB's protective effect, PC-12 cells were treated with Aβ in order to establish an in vitro model of AD. RESULTS: FB-treated mice showed improved learning and memory capacity on both the Morris water maze and object recognition tests. RNA-seq of hippocampal tissue from APP/PS1 mice showed that FB had effects on multiple signaling pathways, specifically decreasing cell apoptotic signaling and increasing AKT and β-catenin signaling. Similarly, FB up-regulated both AKT and β-catenin signaling in PC-12 cells pre-treated with Aβ, in which AKT positively regulated β-catenin signaling. Further study showed that AKT promoted β-catenin signaling via enhancing β-catenin (Ser552) phosphorylation. Moreover, AKT and β-catenin signaling inhibition both resulted in the attenuated survival of FB-treated cells, indicating the AKT/β-catenin signaling is a crucial mediator in FB promoted cell survival. CONCLUSIONS: FB exerted neuroprotective effects on hippocampal cells of APP/PS1 mice, as well as improved cell viability in an in vitro model of AD. The protective actions of FB occurred via the upregulation of AKT/β-catenin signaling.
Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, et al. Recent publications from the alzheimer’s disease neuroimaging initiative: reviewing progress toward improved AD clinical trials. Alzheimers Dementia 2017;13:E1–E85.
[DOI: 10.1016/j.jalz.2016.11.007]
Santos MA, Chand K, Chaves S. Recent progress in repositioning Alzheimer’s disease drugs based on a multitarget strategy. Future Med Chem 2016;8:2113–2142.
[DOI: 10.4155/fmc-2016-0103]
Ward SE, Dawson LA, Konneh M, Macdonald G, Alzheimer’s disease therapeutics—are we making progress towards a disease-modifying treatment for patients? Highlights from the Society for Medicines Research Symposium, held June 20, 2016. Drugs Future 2016;41:461–466.
[DOI: 10.1358/dof.2016.041.07.2516439]
Hane FT, Lee BY, Leonenko Z. Recent progress in Alzheimer’s disease research. Part 1: Pathology. J Alzheimers Dis 2017;57:1–28.
[DOI: 10.3233/JAD-160882]
Mena RJ, Munoz L. Stages of pathological tau-protein processing in Alzheimer’s disease: from soluble aggregations to polymerization into insoluble Tau-PHFs. Current Hypoth Res Milestones Alzheimer’s Dis 2009:79.
Garcia-Sierra F, Mondragon-Rodriguez S, Basurto-Islas G. Truncation of tau protein and its pathological significance in Alzheimer’s disease. J Alzheimers Dis 2008;14:401–409.
[DOI: 10.3233/JAD-2008-14407]
Fares A, Borrmann D. Neurochemical Aspects of Alzheimer’s disease and movement disturbances: a theory of beta-amyloid and tau-protein. Am J Alzheimers Dis 2018;33:535–540.
[DOI: 10.1177/1533317518790631]
Ma HK, Liu Y, Li B, Zhang Y, Sun LJ, Xu FQ. Chinese Medicine for Alzheimer’s disease: a meta-analysis of randomized controlled trials. Chin J Integr Med 2018;24:938–943.
[DOI: 10.1007/s11655-018-2567-4]
Wu JG, Wang YY, Zhang ZL, Yu B. Herbal medicine in the treatment of Alzheimer’s disease. Chin J Integr Med 2015;21:102–107.
[DOI: 10.1007/s11655-014-1337-y]
Hicks D. The relationship between the amyloid precursor protein and tar DNA binding protein 43 (TDP-43): links to Alzheimer’s disease. J Neurochem 2017;142:157–157.
McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J. TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. Brain Pathol 2017;27:472–479.
[DOI: 10.1111/bpa.12424]
Bell W, English C, Ling J, Kageyama Y, Wong, Troncoso J. TDP-43 pathological changes in early onset Alzheimer’s disease and late onset Alzheimer’s disease. J Neuropathol Exp Neurol 2017;76:505.
Wang J, Zhao Z, Lin E, Zhao W, Qian XJ, Freire D, et al. Unintended effects of cardiovascular drugs on the pathogenesis of Alzheimer’s disease. PLoS One 2013;8:e65232.
[DOI: 10.1371/journal.pone.0065232]
May BH, Feng M, Zhou IW, Chang SY, Lu SC, Zhang AL, et al. Memory impairment, dementia, and Alzheimer’s disease in classical and contemporary traditional Chinese medicine. J Alternat Complement Med 2016;22:695–705.
[DOI: 10.1089/acm.2016.0070]
Zhao, HF, Huang LZ, Qin LP, Huang BK. Antioxidative and anti-inflammatory properties of Chushizi oil from Fructus Broussonetiae. J Med Plants Res 2011;5:6407–6412.
Lin LW, Chen HY, Wu CR, Liao PM, Lin YT, Hsieh MT, et al. Comparison with various parts of Broussonetia papyrifera as to the antinociceptive and anti-inflammatory activities in rodents. Biosci Biotechnol Biochem 2008;72:2377–2384.
[DOI: 10.1271/bbb.80276]
Li YH, Hu L, Wu ZZ, Yu ZL, Cao MQ, Sun KH, et al. Fructus Broussonetae extract improves cognitive function and endoplasmic reticulum stress in Alzheimer’s disease models. Neural Regener Res 2011;6:2325–2331.
Jeon, S, Bose S, Hur J, Jun K, Kim YK, Cho KS, et al. A modified formulation of Chinese traditional medicine improves memory impairment and reduces A beta level in the Tg-APPswe/PS1dE9 mouse model of Alzheimer’s disease. J Ethnopharmacol 2011;137:783–789.
[DOI: 10.1016/j.jep.2011.06.046]
Morris R. Developments of a water-maze procedure for studying spatial-learning in the rat. J Neurosci Methods 1984;11:47–60.
[DOI: 10.1016/0165-0270(84)90007-4]
Alamed J, Wilcock DM, Diamond DM, Gordon MN, Morgan D. Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice. Nature Protocols 2006;1:1671–1679.
[DOI: 10.1038/nprot.2006.275]
Hou YJ, Wang Y, Zhao J, Li XH, Cui J, Ding JQ, et al. Smart Soup, a traditional Chinese medicine formula, ameliorates amyloid pathology and related cognitive deficits. PLoS One 2014;9:e111215.
[DOI: 10.1371/journal.pone.0111215]
Kumar P, Nagarajan A, Uchil PD. Analysis of cell viability by the MTT assay. Cold Spring Harb Protoc 2018;2018:095505.
Li L, Zhang L, Yang CC. Multi-target strategy and experimental studies of traditional chinese medicine for Alzheimer’s disease therapy. Curr Topics Med Chem 2016;16:537–548.
[DOI: 10.2174/1568026615666150813144003]
Li L, Zhang L. Action characteristics of traditional Chinese medicine in treatment of Alzheimer’s disease. Progr Biochem Biophy 2012;39:816–828.
[DOI: 10.3724/SP.J.1206.2012.00230]
Liu P, Kong MW, Yuan SH, Liu JF, Wang. History and experience: a survey of traditional chinese medicine treatment for Alzheimer’s disease. Evid Based Complement Alternat Med 2014.
Jiang HL, Luo XM, Bai DL. Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A: a drug of traditional Chinese medicine origin for the treatment of Alzheimer’s disease. Curr Med Chem 2003;10:2231–2252.
[DOI: 10.2174/0929867033456747]
Chen KC, Liu YC, Lee CC, Chen CYC. Potential retinoid X receptor agonists for treating Alzheimer’s disease from traditional Chinese medicine. Evid Based Complement Alternat Med 2014;2014:278493.
[PMID: 24876869]
Huang HJ, Lee CC, Chen CYC. Lead discovery for Alzheimer’s disease related target protein RbAp48 from traditional Chinese medicine. Biomed Res Int 2014;2014:764946.
[PMID: 25165715]
Hou, XQ, Li Y, Qiu JL, Huang F. Evidence from the randomized controlled trials of traditional Chinese medicine compound in treating Alzheimer’s disease. Proceedings of the Ieee/Acm International Conference on Advances in Social Networks Analysis and Mining. Asonam; 2014:752-758.
Zeng LF, Wang NS, Wang Q, Zou YP, Liang ZH, Kong LS, et al. Oral Chinese herbal medicine for kidney nourishment in Alzheimer’s disease: a systematic review of the effect on MMSE index measures and safety. Complement Ther Med 2015;23:283–297.
[DOI: 10.1016/j.ctim.2015.01.014]
Ong WY, Wu YJ, Farooqui T, Farooqui AA. Qi Fu Yin-a Ming dynasty prescription for the treatment of dementia. Molecul Neurobiol 2018;55:7389–7400.
[DOI: 10.1007/s12035-018-0908-0]
Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ. A beta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 2008;59:214–225.
[DOI: 10.1016/j.neuron.2008.06.008]
Berridge MJ. Calcium regulation of neural rhythms, memory and Alzheimer’s disease. J Physiol 2014;592:281–293.
[DOI: 10.1113/jphysiol.2013.257527]
Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Different 2012;19:1880–1891.
[DOI: 10.1038/cdd.2012.74]
