Skip to main content

Advertisement

SpringerLink
Log in

A direct interaction between RhoGDIα/Tau alleviates hyperphosphorylation of Tau in Alzheimer's disease and vascular dementia

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

RhoGDIα is an inhibitor of RhoGDP dissociation that involves in Aβ metabolism and NFTs production in Alzheimer's disease (AD) by regulating of RhoGTP enzyme activity. Our previous research revealed that RhoGDIα, as the target of Polygala saponin (Sen), might alleviate apoptosis of the nerve cells caused by hypoxia/reoxygenation (H/R). To further clarify the role of RhoGDIα in the generation of NFTs, we explored the relationship between RhoGDIα and Tau. We found out that RhoGDIα and Tau can bind with each other and interact by using coimmunoprecipitation (Co-IP) and GST pulldown methods in vitro. This RhoGDIα-Tau partnership was further verified by using immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) approaches in PC12 cells. Using the RNA interference (RNAi) technique, we found that the RhoGDIα may be involved in an upstream signaling pathway for Tau. Subsequently, in Aβ25-35- and H/R-induced PC12 cells, forced expression of RhoGDIα via cDNA plasmid transfection was found to reduce the hyperphosphorylation of Tau, augment the expression of bcl-2 protein, and inhibit the expression of Bax protein (reducing the Bax/bcl-2 ratio) and the activity of caspase-3. In mouse AD and VaD models, forced expression of RhoGDIα via injection of a viral vector (pAAV-EGFP-RhoGDIα) into the lateral ventricle of the brain alleviated the pathological symptoms of AD and VaD. Finally, GST pulldown confirmed that the binding sites on RhoGDIα for Tau were located in the range of the ΔC33 fragment (aa 1–33). These results indicate that RhoGDIα is involved in the phosphorylation of Tau and apoptosis in AD and VaD. Overexpression of RhoGDIα can inhibit the generation of NFTs and delay the progress of these two types of dementia.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Bolognin S, Lorenzetto E, Diana G, Buffelli M (2014) The potential role of rho GTPases in Alzheimer’s disease pathogenesis. Mol Neurobiol 50:406–422

    Article  CAS  PubMed  Google Scholar 

  • Banning C, Votteler J, Hoffmann D, Koppensteiner H, Warmer M, Reimer R, Kirchhoff F, Schubert U, Hauber J, Schindler M (2010) A flow cytometry-based FRET assay to identify and analyse protein-protein interactions in living cells. PLoS One 5:e9344

  • Bond LM, Sellers JR, McKerracher L (2015) Rho kinase as a target for cerebral vascular disorders. Future Med Chem 7:1039–1053

    Article  CAS  PubMed  Google Scholar 

  • Briz V, Zhu G, Wang Y, Liu Y, Avetisyan M, Bi X, Baudry M (2015) Activity-dependent rapid local RhoA synthesis is required for hippocampal synaptic plasticity. J Neurosci 35:2269–2282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cabrales Fontela Y, Kadavath H, Biernat J, Riedel D, Mandelkow E, Zweckstetter M (2017) Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau. Nat Commun 8:1981

    Article  PubMed  PubMed Central  Google Scholar 

  • Chidambaram SB, Rathipriya AG, Bolla SR, Bhat A, Ray B, Mahalakshmi AM, Manivasagam T, Thenmozhi AJ, Essa MM, Guillemin GJ et al (2019) Dendritic spines: Revisiting the physiological role. Prog Neuropsychopharmacol Biol Psychiatry 92:161–193

    Article  CAS  PubMed  Google Scholar 

  • Cho HJ, Kim JT, Baek KE, Kim BY, Lee HG (2019) Regulation of Rho GTPases by RhoGDIs in Human Cancers. Cells 8

  • Congdon EE, Sigurdsson EM (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14:399–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dovas A, Couchman JR (2005) RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem J 390:1–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eisenberg DS, Sawaya MR (2017) Neurodegeneration: Taming tangled tau. Nature 547:170–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Mata R, Boulter E, Burridge K (2011) The invisible hand: regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol 12:493–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamano T, Shirafuji N, Yen SH, Yoshida H, Kanaan NM, Hayashi K, Ikawa M, Yamamura O, Fujita Y, Kuriyama M et al (2020) Rho-kinase ROCK inhibitors reduce oligomeric tau protein. Neurobiol Aging 89:41–54

    Article  CAS  PubMed  Google Scholar 

  • He L, Olson DP, Wu X, Karpova TS, McNally JG, Lipsky PE (2003) A flow cytometric method to detect protein-protein interaction in living cells by directly visualizing donor fluorophore quenching during CFP?YFP fluorescence resonance energy transfer (FRET). Cytometry 55A:71–85

    Article  CAS  Google Scholar 

  • Hensel N, Rademacher S, Claus P (2015) Chatting with the neighbors: crosstalk between Rho-kinase (ROCK) and other signaling pathways for treatment of neurological disorders. Front Neurosci 9:198

    Article  PubMed  PubMed Central  Google Scholar 

  • Herskowitz JH, Feng Y, Mattheyses AL, Hales CM, Higginbotham LA, Duong DM, Montine TJ, Troncoso JC, Thambisetty M, Seyfried NT et al (2013) Pharmacologic inhibition of ROCK2 suppresses amyloid-β production in an Alzheimer’s disease mouse model. J Neurosci 33:19086–19098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huehnchen P, Boehmerle W, Springer A, Freyer D, Endres M (2017) A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice. Trans Psych. 7:e1185

  • Kalpachidou T, Spiecker L, Kress M, Quarta S (2019) Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons. Cells 8

  • Karpova TS, Baumann CT, He L, Wu X, Grammer A, Lipsky P, Hager GL, McNally JG (2003) Fluorescence resonance energy transfer from cyan to yellow fluorescent protein detected by acceptor photobleaching using confocal microscopy and a single laser. J Microsc 209:56–70

    Article  CAS  PubMed  Google Scholar 

  • Kavallaris M (2010) Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 10:194

    Article  CAS  PubMed  Google Scholar 

  • Kellogg EH, Hejab NMA, Poepsel S, Downing KH, DiMaio F, Nogales E (2018) Near-atomic model of microtubule-tau interactions. Science 360:1242–1246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koch JC, Tatenhorst L, Roser AE, Saal KA, Tönges L, Lingor P (2018) ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacol Ther 189:1–21

    Article  CAS  PubMed  Google Scholar 

  • Kuhlmann N, Wroblowski S, Knyphausen P, de Boor S, Brenig J, Zienert AY, Meyer-Teschendorf K, Praefcke GJ, Nolte H, Krüger M et al (2016) Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα by Lysine Acetylation. J Biol Chem 291:5484–5499

    Article  CAS  PubMed  Google Scholar 

  • LI JL, Hui XU, Zhang HP, FU YM, Wang YP, Wang HD, QI RB (2018) Effects of Chinese traditional medicine-selected recipe Q0409 on ability of learning and memory in SAM-P/8 mice. Chinese J Pathophysiol 34:1055–1060

  • LI JL, Hui XU, Zhang HP, FU YM, Wang YP, Wang HD, QI RB (2018) Effects of Chinese traditional medicine-selected recipe Q0409 on ability of learning and memory in SAM-P/8 mice. Chinese J Pathophysiol 34(6):1055–1060., 1055–1060

  • Li X, Zhao Y, Liu P, Zhu X, Chen M, Wang H, Lu D, Qi R (2014) Senegenin Inhibits Hypoxia/Reoxygenation-Induced Neuronal Apoptosis by Upregulating RhoGDIα. Mol Neurobiol 52:1561–1571

    Article  PubMed  Google Scholar 

  • Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J et al (2017) Dementia prevention, intervention, and care. The Lancet 390:2673–2734

    Article  Google Scholar 

  • Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, Beech W, Frautschy SA, Cole GM (2008) p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. J Biol Chem 283:14132–14143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martino A, Ettorre M, Musilli M, Lorenzetto E, Buffelli M, Diana G (2013) Rho GTPase-dependent plasticity of dendritic spines in the adult brain. Front Cell Neurosci 7:62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazanetz MP, Fischer PM (2007) Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discovery 6:464

    Article  CAS  PubMed  Google Scholar 

  • Mueller BK, Mack H, Teusch N (2005) Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4:387–398

    Article  CAS  PubMed  Google Scholar 

  • Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, Kyrargyri V, Pfeiffer T, Khennouf L, Madry C et al. (2019). Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science eaav9518

  • O’Brien JT, Thomas A (2015) Vascular dementia. Lancet 386:1698–1706

    Article  PubMed  Google Scholar 

  • Albayram O, Kondo A, Mannix R, Smith C, Tsai CY, Li C, Zhou XZ (2017) Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nat Commun 8:(1):1–17

  • Olson MF (2008) Applications for ROCK kinase inhibition. Curr Opin Cell Biol 20:242–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paterson HF, Self AJ, Garrett MD, Just I, Aktories K, Hall A (1990) Microinjection of recombinant p21rho induces rapid changes in cell morphology. J Cell Biol 111:1001–1007

    Article  CAS  PubMed  Google Scholar 

  • Polanco JC, Li C, Bodea L-G, Martinez-Marmol R, Meunier FA, Götz J (2017) Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies. Nat Rev Neurol 14:22–39

    Article  PubMed  Google Scholar 

  • Remy I, Michnick SW (2006) A highly sensitive protein-protein interaction assay based on Gaussia luciferase. Nat Methods 3:977–979

    Article  CAS  PubMed  Google Scholar 

  • Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4:446–456

    Article  CAS  PubMed  Google Scholar 

  • Rong F, Li W, Chen K, Li DM, Duan WM, Feng YZ, Li F, Zhou XW, Fan SJ, Liu Y et al (2012) Knockdown of RhoGDIα induces apoptosis and increases lung cancer cell chemosensitivity to paclitaxel. Neoplasma 59:541–550

    Article  CAS  PubMed  Google Scholar 

  • Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388:505–517

    Article  CAS  PubMed  Google Scholar 

  • Switzer CH, Cheng RY, Vitek TM, Christensen DJ, Wink DA, Vitek MP (2011) Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene 30:2504–2513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tatenhorst L, Eckermann K, Dambeck V, Fonseca-Ornelas L, Walle H, Lopes da Fonseca T, Koch JC, Becker S, Tönges L, Bähr M et al (2016) Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease. Acta Neuropathol Commun 4:39

    Article  PubMed  PubMed Central  Google Scholar 

  • ten Klooster JP, Leeuwen I, Scheres N, Anthony EC, Hordijk PL (2007) Rac1-induced cell migration requires membrane recruitment of the nuclear oncogene SET. Embo j 26:336–345

    Article  PubMed  PubMed Central  Google Scholar 

  • van der Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, Scheltens P (2018) Vascular cognitive impairment. Nat Rev Dis Primers 4:18003

    Article  PubMed  Google Scholar 

  • Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang H, Wang B, Liao Q, An H, Li W, Jin X, Cui S, Zhao L (2014) Overexpression of RhoGDI, a novel predictor of distant metastasis, promotes cell proliferation and migration in hepatocellular carcinoma. FEBS Lett 588:503–508

    Article  CAS  PubMed  Google Scholar 

  • Xie F, Shao S, Aziz AUR, Zhang B, Wang H, Liu B (2017) Role of Rho-specific guanine nucleotide dissociation inhibitor α regulation in cell migration. Acta Histochem 119:183–189

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Maruyama K, Himori N, Omodaka K, Yokoyama Y, Shiga Y, Morin R, Nakazawa T (2014) The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol vis Sci 55:7126–7136

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Wang H, Li J, Liu Y, Ding Y (2008) Overexpression of Rho GDP-dissociation inhibitor alpha is associated with tumor progression and poor prognosis of colorectal cancer. J Proteome Res 7:3994–4003

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC et al (2003) Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science 302:1215–1217

    Article  CAS  PubMed  Google Scholar 

  • Zhu XQ, Li XM, Zhao YD, Ji XL, Wang YP, Fu YM, Qi RB (2016) Effects of Senegenin against hypoxia/reoxygenation-induced injury in PC12 cells. Chin J Integr Med 22:353–361

Download references

Acknowledgements

The authors thank all participants of the present study as well as all members of staff of the Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine.

Funding

This work was supported by the Natural Science Foundation of Guangdong province (No. 2014A030313394), the Project of Science and Technology of Guangzhou (2014J4100098), and the Fundamental Research Funds for the Central Universities in China (No. 21613401).

Author information

Author notes

  1. Heping Zhang, Fan Lu, Panhong Liu, Zhaohui Qiu, Jianling Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China

    Heping Zhang, Panhong Liu, Zhaohui Qiu, Jianling Li, Xiaotong Wang, Hui Xu, Yandong Zhao, Xuemin Li, Huadong Wang, Daxiang Lu & Renbin Qi

  2. Department of Emergency, First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China

    Fan Lu

  3. Department of Pathology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China

    Panhong Liu

  4. Department of Pathology, The Eighth Affiliated Hospital, Sun Yat-Sen University, ShenZhen, 518033, China

    Zhaohui Qiu

  5. Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, 510630, China

    Jianling Li

  6. Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China

    Yandong Zhao

  7. High Magnetic Field Laboratory, Chinese Academy of Sciences, Anhui, 230031, China

    Xuemin Li

Authors
  1. Heping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Panhong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhaohui Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianling Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaotong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yandong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xuemin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Huadong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daxiang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Renbin Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Renbin Qi designed the study, performed the measurements and wrote the manuscript. Heping Zhang performed the measurements and wrote the manuscript. Panhong Liu performed the experiments in vitro and wrote the manuscript. Fan Lu, Zhaohui Qiu analysed and interpreted the data. Jianling Li performed experimental design and animal model replication. Yandong Zhao performed the experiments in vitro. Xiaotong Wang and Hui Xu performed the experiments in vivo. Xuemin Li performed the measurements. Huadong Wang and Daxiang Lu helped with the data analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Renbin Qi.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 10893 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, H., Lu, F., Liu, P. et al. A direct interaction between RhoGDIα/Tau alleviates hyperphosphorylation of Tau in Alzheimer's disease and vascular dementia. J Neuroimmune Pharmacol 18, 58–71 (2023). https://doi.org/10.1007/s11481-021-10049-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-021-10049-w

Keywords

Search

Navigation