Skip to main content

Advertisement

SpringerLink
Log in

Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer’s Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer’s disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE. Alzheimer’s disease. Lancet 2021, 397: 1577–1590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Long JM, Holtzman DM. Alzheimer disease: An update on pathobiology and treatment strategies. Cell 2019, 179: 312–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cummings J, Lee G, Nahed P, Kambar MEZN, Zhong K, Fonseca J, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement (N Y) 2022, 8: e12295.

    Article  PubMed  Google Scholar 

  4. Wang W, Zhao F, Ma X, Perry G, Zhu X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. Mol Neurodegener 2020, 15: 30.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sharma C, Kim S, Nam Y, Jung UJ, Kim SR. Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer’s disease. Int J Mol Sci 2021, 22: 4850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ashleigh T, Swerdlow RH, Beal MF. The role of mitochondrial dysfunction in Alzheimer’s disease pathogenesis. Alzheimer’s Dement 2022, 19: 333–342.

    Article  Google Scholar 

  7. Miller B, Kim SJ, Mehta HH, Cao K, Kumagai H, Thumaty N, et al. Mitochondrial DNA variation in Alzheimer’s disease reveals a unique microprotein called SHMOOSE. Mol Psychiatry 2023, 28: 1813–1826.

    Article  CAS  PubMed  Google Scholar 

  8. Wang D, Wang Z, Zhang L, Li Z, Tian X, Fang J, et al. Cellular ATP levels are affected by moderate and strong static magnetic fields. Bioelectromagnetics 2018, 39: 352–360.

    Article  CAS  PubMed  Google Scholar 

  9. Zhu X, Liu Y, Cao X, Liu H, Sun A, Shen H, et al. Moderate static magnetic fields enhance antitumor CD8+ T cell function by promoting mitochondrial respiration. Sci Rep 2020, 10: 14519.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cao H, Zuo C, Gu Z, Huang Y, Yang Y, Zhu L, et al. High frequency repetitive transcranial magnetic stimulation alleviates cognitive deficits in 3xTg-AD mice by modulating the PI3K/Akt/GLT-1 axis. Redox Biol 2022, 54: 102354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lenz M, Galanis C, Müller-Dahlhaus F, Opitz A, Wierenga CJ, Szabó G, et al. Repetitive magnetic stimulation induces plasticity of inhibitory synapses. Nat Commun 2016, 7: 10020.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pell GS, Roth Y, Zangen A. Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: Influence of timing and geometrical parameters and underlying mechanisms. Prog Neurobiol 2011, 93: 59–98.

    Article  PubMed  Google Scholar 

  13. Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018). Clin Neurophysiol 2020, 131: 474–528.

    Article  PubMed  Google Scholar 

  14. Dufor T, Grehl S, Tang AD, Doulazmi M, Traoré M, Debray N, et al. Neural circuit repair by low-intensity magnetic stimulation requires cellular magnetoreceptors and specific stimulation patterns. Sci Adv 2019, 5: eaav9847.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu X, Ji GJ, Geng Z, Wang L, Yan Y, Wu Y, et al. Accelerated intermittent theta-burst stimulation broadly ameliorates symptoms and cognition in Alzheimer’s disease: A randomized controlled trial. Brain Stimul 2022, 15: 35–45.

    Article  PubMed  Google Scholar 

  16. Golaszewski S, Kunz A, Schwenker K, Sebastianelli L, Versace V, Ferrazzoli D, et al. Effects of intermittent Theta burst stimulation on the clock drawing test performances in patients with alzheimer’s disease. Brain Topogr 2021, 34: 461–466.

    Article  PubMed  Google Scholar 

  17. Leblhuber F, Geisler S, Ehrlich D, Steiner K, Kurz K, Fuchs D. High frequency repetitive transcranial magnetic stimulation improves cognitive performance parameters in patients with Alzheimer’s disease - an exploratory pilot study. Curr Alzheimer Res 2022: 681–688.

  18. Suraci D, Saudino G, Nasta V, Ciofi-Baffoni S, Banci L. ISCA1 orchestrates ISCA2 and NFU1 in the maturation of human mitochondrial[4Fe-4S]proteins. J Mol Biol 2021, 433: 166924.

    Article  CAS  PubMed  Google Scholar 

  19. Sheftel AD, Wilbrecht C, Stehling O, Niggemeyer B, Elsässer HP, Mühlenhoff U, et al. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for[4Fe-4S]protein maturation. Mol Biol Cell 2012, 23: 1157–1166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Beilschmidt LK, Ollagnier de Choudens S, Fournier M, Sanakis I, Hograindleur MA, Clémancey M, et al. ISCA1 is essential for mitochondrial Fe4S4 biogenesis in vivo. Nat Commun 2017, 8: 15124.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  21. Shukla A, Hebbar M, Srivastava A, Kadavigere R, Upadhyai P, Kanthi A, et al. Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. J Hum Genet 2017, 62: 723–727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lebigot E, Hully M, Amazit L, Gaignard P, Michel T, Rio M, et al. Expanding the phenotype of mitochondrial disease: Novel pathogenic variant in ISCA1 leading to instability of the iron-sulfur cluster in the protein. Mitochondrion 2020, 52: 75–82.

    Article  CAS  PubMed  Google Scholar 

  23. Qin S, Yin H, Yang C, Dou Y, Liu Z, Zhang P, et al. A magnetic protein biocompass. Nat Mater 2016, 15: 217–226.

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Long X, Ye J, Zhao D, Zhang SJ. Magnetogenetics: Remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor. Sci Bull 2015, 60: 2107–2119.

    Article  CAS  Google Scholar 

  25. Zhang C, Lu R, Wang L, Yun W, Zhou X. Restraint devices for repetitive transcranial magnetic stimulation in mice and rats. Brain Behav 2019, 9: e01305.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gersner R, Kravetz E, Feil J, Pell G, Zangen A. Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: Differential outcomes in anesthetized and awake animals. J Neurosci 2011, 31: 7521–7526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jiao SS, Yao XQ, Liu YH, Wang QH, Zeng F, Lu JJ, et al. Edaravone alleviates Alzheimer’s disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A 2015, 112: 5225–5230.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gao SH, Tao Y, Zhu Y, Huang H, Shen LL, Gao CY. Activation of dopamine D2 receptors alleviates neuronal hyperexcitability in the lateral entorhinal cortex via inhibition of HCN current in a rat model of chronic inflammatory pain. Neurosci Bull 2022, 38: 1041–1056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang YJ, Pollard A, Zhong JH, Dong XY, Wu XB, Zhou HD, et al. Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer’s disease. Neurobiol Aging 2009, 30: 364–376.

    Article  PubMed  Google Scholar 

  30. Zhu Y, Gao M, Huang H, Gao SH, Liao LY, Tao Y, et al. p75NTR ectodomain ameliorates cognitive deficits and pathologies in a rapid eye movement sleep deprivation mice model. Neuroscience 2022, 496: 27–37.

    Article  CAS  PubMed  Google Scholar 

  31. Neitemeier S, Jelinek A, Laino V, Hoffmann L, Eisenbach I, Eying R, et al. BID links ferroptosis to mitochondrial cell death pathways. Redox Biol 2017, 12: 558–570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao CG, Qin J, Sun W, Ju F, Zhao YL, Wang R, et al. rTMS regulates the balance between proliferation and apoptosis of spinal cord derived neural stem/progenitor cells. Front Cell Neurosci 2020, 13: 584.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Grover S, Wen W, Viswanathan V, Gill CT, Reinhart RMG. Long-lasting, dissociable improvements in working memory and long-term memory in older adults with repetitive neuromodulation. Nat Neurosci 2022, 25: 1237–1246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li X, Qi G, Yu C, Lian G, Zheng H, Wu S, et al. Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment. Brain Stimul 2021, 14: 503–510.

    Article  PubMed  Google Scholar 

  35. Yao Q, Tang F, Wang Y, Yan Y, Dong L, Wang T, et al. Effect of cerebellum stimulation on cognitive recovery in patients with Alzheimer disease: A randomized clinical trial. Brain Stimul 2022, 15: 910–920.

    Article  PubMed  Google Scholar 

  36. Berry BJ, Trewin AJ, Milliken AS, Baldzizhar A, Amitrano AM, Lim Y, et al. Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance. EMBO Rep 2020, 21: e49113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Berry BJ, Vodičková A, Müller-Eigner A, Meng C, Ludwig C, Kaeberlein M, et al. Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan. Nat Aging 2023, 3: 157–161.

    Article  PubMed  Google Scholar 

  38. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997, 42: 85–94.

    Article  CAS  PubMed  Google Scholar 

  39. An Y, Varma VR, Varma S, Casanova R, Dammer E, Pletnikova O, et al. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement 2018, 14: 318–329.

    Article  PubMed  Google Scholar 

  40. Chen P, Shen Z, Wang Q, Zhang B, Zhuang Z, Lin J, et al. Reduced cerebral glucose uptake in an alzheimer’s rat model with glucose-weighted chemical exchange saturation transfer imaging. Front Aging Neurosci 2021, 13: 618690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shivamurthy VKN, Tahari AK, Marcus C, Subramaniam RM. Brain FDG PET and the diagnosis of dementia. AJR Am J Roentgenol 2015, 204: W76–W85.

    Article  PubMed  Google Scholar 

  42. He C, Li Q, Cui Y, Gao P, Shu W, Zhou Q, et al. Recurrent moderate hypoglycemia accelerates the progression of Alzheimer’s disease through impairment of the TRPC6/GLUT3 pathway. JCI Insight 2022, 7: e154595.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Xu A, Tang Y, Zeng Q, Wang X, Tian H, Zhou Y, et al. Electroacupuncture enhances cognition by promoting brain glucose metabolism and inhibiting inflammation in the APP/PS1 mouse model of alzheimer’s disease: A pilot study. J Alzheimers Dis 2020, 77: 387–400.

    Article  CAS  PubMed  Google Scholar 

  44. Nolfi-Donegan D, Braganza A, Shiva S. Nolfi-Donegan, Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol 2020, 37: 101674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron 2005, 45: 201–206.

    Article  CAS  PubMed  Google Scholar 

  46. Koch G, Bonnì S, Casula EP, Iosa M, Paolucci S, Pellicciari MC, et al. Effect of cerebellar stimulation on gait and balance recovery in patients with hemiparetic stroke: A randomized clinical trial. JAMA Neurol 2019, 76: 170–178.

    Article  PubMed  Google Scholar 

  47. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 2008, 321: 1686–1689.

    Article  ADS  CAS  PubMed  Google Scholar 

  48. Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2012, 109: 8740–8745.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 2007, 55: 697–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kann O, Kovács R. Mitochondria and neuronal activity. Am J Physiol Cell Physiol 2007, 292: C641–C657.

    Article  CAS  PubMed  Google Scholar 

  51. Lill R, Freibert SA. Mechanisms of mitochondrial iron-sulfur protein biogenesis. Annu Rev Biochem 2020, 89: 471–499.

    Article  CAS  PubMed  Google Scholar 

  52. Lill R. Function and biogenesis of iron-sulphur proteins. Nature 2009, 460: 831–838.

    Article  ADS  CAS  PubMed  Google Scholar 

  53. Webert H, Freibert SA, Gallo A, Heidenreich T, Linne U, Amlacher S, et al. Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin. Nat Commun 2014, 5: 5013.

    Article  ADS  CAS  PubMed  Google Scholar 

  54. Rosenfeld M, Brenner-Lavie H, Ari SGB, Kavushansky A, Ben-Shachar D. Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia. Biol Psychiatry 2011, 69: 980–988.

    Article  CAS  PubMed  Google Scholar 

  55. Sharma K, Chandra A, Hasija Y, Saini N. MicroRNA-128 inhibits mitochondrial biogenesis and function via targeting PGC1α and NDUFS4. Mitochondrion 2021, 60: 160–169.

    Article  CAS  PubMed  Google Scholar 

  56. Karmi O, Marjault HB, Bai F, Roy S, Sohn YS, Darash Yahana M, et al. A VDAC1-mediated NEET protein chain transfers[2Fe-2S]clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics. Proc Natl Acad Sci U S A 2022, 119: e2121491119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huang Z, Tan T, Du Y, Chen L, Fu M, Yu Y, et al. Low-frequency repetitive transcranial magnetic stimulation ameliorates cognitive function and synaptic plasticity in APP23/PS45 mouse model of alzheimer’s disease. Front Aging Neurosci 2017, 9: 292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lin Y, Jin J, Lv R, Luo Y, Dai W, Li W, et al. Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun 2021, 9: 102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Swerdlow RH. Mitochondria and mitochondrial cascades in Alzheimer’s disease. J Alzheimers Dis 2018, 62: 1403–1416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 1994, 269: 13623–13628.

    Article  CAS  PubMed  Google Scholar 

  61. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016, 8: 595–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hong Y, Liu Q, Peng M, Bai M, Li J, Sun R, et al. High-frequency repetitive transcranial magnetic stimulation improves functional recovery by inhibiting neurotoxic polarization of astrocytes in ischemic rats. J Neuroinflammation 2020, 17: 150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Luo L, Liu M, Fan Y, Zhang J, Liu L, Li Y, et al. Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice. J Neuroinflammation 2022, 19: 141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen X, Dong GY, Wang LX. High-frequency transcranial magnetic stimulation protects APP/PS1 mice against Alzheimer’s disease progress by reducing APOE and enhancing autophagy. Brain Behav 2020, 10: e01740.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Li K, Wang X, Jiang Y, Zhang X, Liu Z, Yin T, et al. Early intervention attenuates synaptic plasticity impairment and neuroinflammation in 5xFAD mice. J Psychiatr Res 2021, 136: 204–216.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81901142) and funds for key support objects of Third Military Medical University.

Author information

Author notes

  1. Yang Zhu and Hao Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Yang Zhu, Hao Huang, Yong Tao, Ling-Yi Liao, Shi-Hao Gao & Chang-Yue Gao

  2. Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Yan-Jiang Wang

  3. Department of Special Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Zhi Chen

Authors
  1. Yang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling-Yi Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shi-Hao Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan-Jiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chang-Yue Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shi-Hao Gao, Yan-Jiang Wang or Chang-Yue Gao.

Ethics declarations

Conflict of interest

The authors declare that there are no conflict of interest.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Y., Huang, H., Chen, Z. et al. Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer’s Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice. Neurosci. Bull. 40, 182–200 (2024). https://doi.org/10.1007/s12264-023-01098-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-023-01098-7

Keywords

Search

Navigation