Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer’s disease

Wei Xiong1, Ye Liu1, Heng Zhou1, Junyi Li1, Shuili Jing1, Cailei Jiang2, Mei Li3, Yan He2,4, Qingsong Ye1,5

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International Journal of Oral Science ›› 2024, Vol. 16 ›› Issue (0) : 40. DOI: 10.1038/s41368-024-00300-4

Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer’s disease

  • Wei Xiong1, Ye Liu1, Heng Zhou1, Junyi Li1, Shuili Jing1, Cailei Jiang2, Mei Li3, Yan He2,4, Qingsong Ye1,5
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Abstract

Oxidative stress is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease (AD), particularly in the early stages of the disease. The multiplicity advantages of stem cell transplantation make it fascinating therapeutic strategy for many neurodegenerative diseases. We herein demonstrated that human dental pulp stem cells (hDPSCs) mediated oxidative stress improvement and neuroreparative effects in in vitro AD models, playing critical roles in regulating the polarization of hyperreactive microglia cells and the recovery of damaged neurons. Importantly, these therapeutic effects were reflected in 10-month-old 3xTg-AD mice after a single transplantation of hDPSCs, with the treated mice showing significant improvement in cognitive function and neuropathological features. Mechanistically, antioxidant and neuroprotective effects, as well as cognitive enhancements elicited by hDPSCs, were at least partially mediated by Nrf2 nuclear accumulation and downstream antioxidant enzymes expression through the activation of the AKT-GSK3β-Nrf2 signaling pathway. In conclusion, our findings corroborated the neuroprotective capacity of hDPSCs to reshape the neuropathological microenvironment in both in vitro and in vivo AD models, which may be a tremendous potential therapeutic candidate for Alzheimer’s disease.

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Wei Xiong, Ye Liu, Heng Zhou, Junyi Li, Shuili Jing, Cailei Jiang, Mei Li, Yan He, …Qingsong Ye. Human dental pulp stem cells mitigate the neuropathology and cognitive decline via AKT-GSK3β-Nrf2 pathways in Alzheimer’s disease. International Journal of Oral Science, 2024, 16(0): 40 https://doi.org/10.1038/s41368-024-00300-4

References

1. Xiong, W.et al.Alzheimer’s disease: pathophysiology and dental pulp stem cells therapeutic prospects.Front. Cell Dev. Biol. 10, 999024(2022).
2. Dewanjee, S.et al.Altered glucose metabolism in Alzheimer’s disease: role of mitochondrial dysfunction and oxidative stress.Free Radic. Biol. Med. 193, 134-157 (2022).
3. Butterfield D. A.& Halliwell, B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease.Nat. Rev. Neurosci. 20, 148-160 (2019).
4. Huang, W. J., Zhang, X.& Chen, W. W. Role of oxidative stress in Alzheimer’s disease.Biomed. Rep. 4, 519-522 (2016).
5. Park, M. W.et al.NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases.Redox Biol. 41, 101947(2021).
6. Gowda, P., Reddy, P. H.& Kumar, S. Deregulated mitochondrial microRNAs in Alzheimer’s disease: focus on synapse and mitochondria.Ageing Res Rev. 73, 101529(2022).
7. Bahn, G.et al.NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models.Proc. Natl Acad. Sci. USA 116, 12516-12523 (2019).
8. Liao, S.et al.A novel compound DBZ ameliorates neuroinflammation in LPS-stimulated microglia and ischemic stroke rats: role of Akt(Ser473)/GSK3beta(Ser9)-mediated Nrf2 activation.Redox Biol. 36, 101644(2020).
9. Ramsey, C. P.et al.Expression of Nrf2 in neurodegenerative diseases.J. Neuropathol. Exp. Neurol. 66, 75-85 (2007).
10. Kanninen, K.et al.Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease.Proc. Natl Acad. Sci. USA 106, 16505-16510 (2009).
11. Uccelli A., Benvenuto F., Laroni A.& Giunti, D. Neuroprotective features of mesenchymal stem cells.Best. Pr. Res Clin. Haematol. 24, 59-64 (2011).
12. Jia, Y.et al.HGF mediates clinical-grade human umbilical cord-derived mesenchymal stem cells improved functional recovery in a senescence-accelerated mouse model of Alzheimer’s disease.Adv. Sci. 7, 1903809(2020).
13. Lee, J. K.et al.Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses.Stem Cells 28, 329-343 (2010).
14. Shi, Y.et al.Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.J. Exp. Med. 216, 2546-2561 (2019).
15. Hanisch U. K.& Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain.Nat. Neurosci. 10, 1387-1394 (2007).
16. Pan, L. L.et al.Shizukaol B, an active sesquiterpene from Chloranthus henryi, attenuates LPS-induced inflammatory responses in BV2 microglial cells.Biomed. Pharmacother. 88, 878-884 (2017).
17. Kim K. W., Lee Y. S., Choi B. R., Yoon, D. & Lee, D. Y. Anti-neuroinflammatory effect of the ethanolic extract of black ginseng through TLR4-MyD88-regulated inhibition of NF-kappaB and MAPK signaling pathways in LPS-induced BV2 microglial cells. Int. J. Mol. Sci. https://doi.org/10.3390/ijms242015320 (2023).
18. Vasic, V., Barth, K. & Schmidt, M. H. H. Neurodegeneration and neuro-regeneration-Alzheimer’s disease and stem cell therapy. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20174272 (2019).
19. Yang X., Xu S., Qian Y.& Xiao, Q. Resveratrol regulates microglia M1/M2 polarization via PGC-1alpha in conditions of neuroinflammatory injury.Brain Behav. Immun. 64, 162-172 (2017).
20. Peace, C. G. & O’Neill, L. A. The role of itaconate in host defense and inflammation. J. Clin. Invest. https://doi.org/10.1172/JCI148548 (2022).
21. Ahmed S. M., Luo L., Namani A., Wang X. J.& Tang, X. Nrf2 signaling pathway: pivotal roles in inflammation.Biochim. Biophys. Acta Mol. Basis Dis. 1863, 585-597 (2017).
22. Farhat F., Nofal S., Raafat E. M.& Eissa Ahmed, A. A. Akt/GSK3beta/Nrf2/HO-1 pathway activation by flurbiprofen protects the hippocampal neurons in a rat model of glutamate excitotoxicity.Neuropharmacology 196, 108654(2021).
23. Millan Solano, M. V.et al. Effect of systemic inflammation in the CNS: a silent history of neuronal damage. Int. J. Mol. Sci. https://doi.org/10.3390/ijms241511902 (2023).
24. Bian, Y.et al.Oxyphylla A ameliorates cognitive deficits and alleviates neuropathology via the Akt-GSK3beta and Nrf2-Keap1-HO-1 pathways in vitro and in vivo murine models of Alzheimer’s disease.J. Adv. Res. 34, 1-12 (2021).
25. Appel S. H., Zhao W., Beers D. R.& Henkel, J. S. The microglial-motoneuron dialogue in ALS.Acta Myol. 30, 4-8 (2011).
26. Hu, N. W., Ondrejcak, T.& Rowan, M. J. Glutamate receptors in preclinical research on Alzheimer’s disease: update on recent advances.Pharm. Biochem. Behav. 100, 855-862 (2012).
27. Du, W.et al.Engineering of electrospun nanofiber scaffolds for repairing brain injury.Eng. Regen. 4, 289-303 (2023).
28. Navarro A.& Boveris, A. The mitochondrial energy transduction system and the aging process.Am. J. Physiol. Cell Physiol. 292, C670-C686 (2007).
29. Swerdlow, R. H., Burns, J. M.& Khan, S. M. The Alzheimer’s disease mitochondrial cascade hypothesis.J. Alzheimers Dis. 20, S265-S279 (2010).
30. Mehta A., Prabhakar M., Kumar P., Deshmukh R.& Sharma, P. L. Excitotoxicity: bridge to various triggers in neurodegenerative disorders.Eur. J. Pharm. 698, 6-18 (2013).
31. Qiu, J.et al.Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals.Nat. Commun. 4, 2034(2013).
32. Mattson M. P.Pathways towards and away from Alzheimer’s disease.Nature 430, 631-639 (2004).
33. Cheignon, C.et al.Oxidative stress and the amyloid beta peptide in Alzheimer’s disease.Redox Biol. 14, 450-464 (2018).
34. Santamaria, G.et al.Intranasal delivery of mesenchymal stem cell secretome repairs the brain of Alzheimer’s mice.Cell Death Differ. 28, 203-218 (2021).
35. Penzes P., Cahill M. E., Jones K. A., VanLeeuwen, J. E. & Woolfrey, K. M. Dendritic spine pathology in neuropsychiatric disorders.Nat. Neurosci. 14, 285-293 (2011).
36. Lim, J. Y.et al.Potential application of human neural crest-derived nasal turbinate stem cells for the treatment of neuropathology and impaired cognition in models of Alzheimer’s disease.Stem Cell Res. Ther. 12, 402(2021).
37. Keating A.Mesenchymal stromal cells: new directions.Cell Stem Cell 10, 709-716 (2012).
38. Niraula, A., Sheridan, J. F.& Godbout, J. P. Microglia priming with aging and stress.Neuropsychopharmacology 42, 318-333 (2017).
39. Sochocka, M., Diniz, B. S.& Leszek, J. Inflammatory response in the CNS: friend or foe?Mol. Neurobiol. 54, 8071-8089 (2017).
40. Adibhatla R. M.& Hatcher, J. F. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities.Antioxid. Redox Signal 12, 125-169 (2010).
41. Huang, Q.et al.Pathological BBB crossing melanin-like nanoparticles as metal-ion chelators and neuroinflammation regulators against Alzheimer’s disease.Research 6, 0180(2023).
42. Spires-Jones, T. L. & Hyman, B. T. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease.Neuron 82, 756-771 (2014).
43. Tonelli, C., Chio, I. I.C. & Tuveson, D. A. Transcriptional Regulation by Nrf2.Antioxid. Redox Signal 29, 1727-1745 (2018).
44. Brazil, D. P., Yang, Z. Z.& Hemmings, B. A. Advances in protein kinase B signalling: AKTion on multiple fronts.Trends Biochem. Sci. 29, 233-242 (2004).
45. Zou, Y.et al.Protective effect of puerarin against beta-amyloid-induced oxidative stress in neuronal cultures from rat hippocampus: involvement of the GSK-3beta/Nrf2 signaling pathway.Free Radic. Res. 47, 55-63 (2013).
46. Gameiro, I.et al.Discovery of the first dual GSK3beta inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease.Sci. Rep. 7, 45701(2017).
47. Belfiore, R.et al.Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice.Aging Cell 18, e12873(2019).
48. Wu X., Xu Y., Chen G., Tan Q.& Zhu, Y. Transplanted brain organoids become mature and intelligent.Biomed. Technol. 1, 48-51 (2023).
49. Shu, Y.et al.Metal protoporphyrin-induced self-assembly nanoprobe enabling precise tracking and antioxidant protection of stem cells for ischemic stroke therapy. Smart Med. https://doi.org/10.1002/SMMD.20220037(2023).
50. Wang Z. B., Wang Z. T., Sun Y., Tan L.& Yu, J. T. The future of stem cell therapies of Alzheimer’s disease.Ageing Res. Rev. 80, 101655(2022).
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