Skip to main content

Advertisement

SpringerLink
Log in

Role of TPEN in Amyloid-β25–35-Induced Neuronal Damage Correlating with Recovery of Intracellular Zn2+ and Intracellular Ca2+ Overloading

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The overproduction of neurotoxic amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer’s disease (AD). To determine the role of intracellular zinc ion (iZn2+) dysregulation in mediating Aβ-related neurotoxicity, this study aimed to investigate whether N, N, N′, N′‑tetrakis (2‑pyridylmethyl) ethylenediamine (TPEN), a Zn2+‑specific chelator, could attenuate Aβ25–35‑induced neurotoxicity and the underlying mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of primary hippocampal neurons. We also determined intracellular Zn2+ and Ca2+ concentrations, mitochondrial and lysosomal functions, and intracellular reactive oxygen species (ROS) content in hippocampal neurons using live-cell confocal imaging. We detected L-type voltage-gated calcium channel currents (L-ICa) in hippocampal neurons using the whole‑cell patch‑clamp technique. Furthermore, we measured the mRNA expression levels of proteins related to the iZn2+ buffer system (ZnT-3, MT-3) and voltage-gated calcium channels (Cav1.2, Cav1.3) in hippocampal neurons using RT-PCR. The results showed that TPEN attenuated Aβ25–35‑induced neuronal death, relieved the Aβ25–35‑induced increase in intracellular Zn2+ and Ca2+ concentrations; reversed the Aβ25–35‑induced increase in ROS content, the Aβ25–35‑induced increase in the L-ICa peak amplitude at different membrane potentials, the Aβ25–35‑induced the dysfunction of the mitochondria and lysosomes, and the Aβ25–35‑induced decrease in ZnT-3 and MT-3 mRNA expressions; and increased the Cav1.2 mRNA expression in the hippocampal neurons. These results suggest that TPEN, the Zn2+-specific chelator, attenuated Aβ25–35‑induced neuronal damage, correlating with the recovery of intracellular Zn2+ and modulation of abnormal Ca2+-related signaling pathways.

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
Fig. 9

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

References

  1. Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44(1):181–193. https://doi.org/10.1016/j.neuron.2004.09.010

    Article  CAS  PubMed  Google Scholar 

  2. Swerdlow RH (2007) Pathogenesis of Alzheimer’s disease. Clin Interv Aging 2(3):347–359

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Yamasaki T, Muranaka H, Kaseda Y, Mimori Y, Tobimatsu S (2012) Understanding the pathophysiology of Alzheimer’s disease and mild cognitive impairment: a mini review on fMRI and ERP studies. Neurol Res Int 2012:719056. https://doi.org/10.1155/2012/719056

    Article  PubMed  Google Scholar 

  4. Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fülöp L, Penke B, Zilberter Y et al (2009) Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci 29(11):3453–3462. https://doi.org/10.1523/jneurosci.5215-08,2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Praticò D (2008) Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci 29(12):609–615. https://doi.org/10.1016/j.tips.2008.09.001

    Article  CAS  PubMed  Google Scholar 

  6. Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2(7):a006338. https://doi.org/10.1101/cshperspect.a006338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Narayanan SE, Rehuman NA, Harilal S, Vincent A, Rajamma RG, Behl T, Uddin MS, Ashraf GM, Mathew B (2020) Molecular mechanism of zinc neurotoxicity in Alzheimer’s disease. Environ Sci Pollut Res Int 27(35):43542–43552. https://doi.org/10.1007/s11356-020-10477-w

    Article  CAS  PubMed  Google Scholar 

  8. Tyszka-Czochara M, Grzywacz A, Gdula-Argasińska J, Librowski T, Wiliński B, Opoka W (2014) The role of zinc in the pathogenesis and treatment of central nervous system (CNS) diseases. Implications of zinc homeostasis for proper CNS function. Acta Pol Pharm 71(3):369–377

    PubMed  Google Scholar 

  9. Tamano H, Oneta N, Shioya A, Adlard PA, Bush AI, Takeda A (2019) In vivo synaptic activity-independent co-uptakes of amyloid β(1–42) and Zn(2+) into dentate granule cells in the normal brain. Sci Rep 9(1):6498. https://doi.org/10.1038/s41598-019-43012-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. McCord MC, Aizenman E (2014) The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front Aging Neurosci 6:77. https://doi.org/10.3389/fnagi.2014.00077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Deibel MA, Ehmann WD, Markesbery WR (1996) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. J Neurol Sci 143(1–2):137–142. https://doi.org/10.1016/s0022-510x(96)00203-1

    Article  CAS  PubMed  Google Scholar 

  12. Hane F, Leonenko Z (2014) Effect of metals on kinetic pathways of amyloid-β aggregation. Biomolecules 4(1):101–116. https://doi.org/10.3390/biom4010101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29(13):4004–4015. https://doi.org/10.1523/jneurosci.5980-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Berridge MJ (1998) Neuronal calcium signaling. Neuron 21(1):13–26. https://doi.org/10.1016/s0896-6273(00)80510-3

    Article  CAS  PubMed  Google Scholar 

  15. Supnet C, Bezprozvanny I (2010) The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium 47(2):183–189. https://doi.org/10.1016/j.ceca.2009.12.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Popugaeva E, Chernyuk D, Bezprozvanny I (2020) Reversal of calcium dysregulation as potential approach for treating Alzheimer’s disease. Curr Alzheimer Res 17(4):344–354. https://doi.org/10.2174/1567205017666200528162046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Popugaeva E, Pchitskaya E, Bezprozvanny I (2018) Dysregulation of intracellular calcium signaling in Alzheimer’s disease. Antioxid Redox Signal 29(12):1176–1188. https://doi.org/10.1089/ars.2018.7506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alzheimer’s Association Calcium Hypothesis Workgroup （2017）Calcium hypothesis of Alzheimer's disease and brain aging: a framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimer's Dement 13(2):178–182. https://doi.org/10.1016/j.jalz.2016.12.006

  19. Jadiya P, Kolmetzky DW, Tomar D, Di Meco A, Lombardi AA, Lambert JP, Luongo TS, Ludtmann MH et al (2019) Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease. Nat Commun 10(1):3885. https://doi.org/10.1038/s41467-019-11813-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Foster TC, Kyritsopoulos C, Kumar A (2017) Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease. Behav Brain Res 322(Pt B):223–232. https://doi.org/10.1016/j.bbr.2016.05.012

    Article  CAS  PubMed  Google Scholar 

  21. Anekonda TS, Quinn JF, Harris C, Frahler K, Wadsworth TL, Woltjer RL (2011) L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol Dis 41(1):62–70. https://doi.org/10.1016/j.nbd.2010.08.020

    Article  CAS  PubMed  Google Scholar 

  22. Cai Q, Jeong YY (2020) Mitophagy in Alzheimer’s disease and other age-related neurodegenerative diseases. Cells 9(1):150(1-28). https://doi.org/10.3390/cells9010150

  23. Tang Y, Zucker RS (1997) Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron 18(3):483–491. https://doi.org/10.1016/s0896-6273(00)81248-9

    Article  CAS  PubMed  Google Scholar 

  24. Kang JS, Tian JH, Pan PY, Zald P, Li C, Deng C, Sheng ZH (2008) Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132(1):137–148. https://doi.org/10.1016/j.cell.2007.11.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tönnies E, Trushina E (2017) Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimer’s Dis JAD 57(4):1105–1121. https://doi.org/10.3233/jad-161088

    Article  PubMed  Google Scholar 

  26. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. https://doi.org/10.1038/nature05292

    Article  CAS  PubMed  Google Scholar 

  27. Swerdlow RH, Burns JM, Khan SM (2010) The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimer’s Dis JAD 20(Suppl 2):S265-279. https://doi.org/10.3233/jad-2010-100339

    Article  PubMed  Google Scholar 

  28. Swerdlow RH, Burns JM (1842) Khan SM (2014) The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochem Biophys Acta 8:1219–1231. https://doi.org/10.1016/j.bbadis.2013.09.010

    Article  CAS  Google Scholar 

  29. Chen WB, Wang YX, Wang HG, An D, Sun D, Li P, Zhang T, Lu WG et al (2021) TPEN attenuates amyloid-β(25–35)-induced neuronal damage with changes in the electrophysiological properties of voltage-gated sodium and potassium channels. Mol Brain 14(1):124. https://doi.org/10.1186/s13041-021-00837-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  31. Tamano H, Nishio R, Shakushi Y, Sasaki M, Koike Y, Osawa M, Takeda A (2017) In vitro and in vivo physiology of low nanomolar concentrations of Zn2+ in artificial cerebrospinal fluid. Sci Rep 7:42897. https://doi.org/10.1038/srep42897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Frederickson CJ, Giblin LJ, Krezel A, McAdoo DJ, Mueller RN, Zeng Y, Balaji RV, Masalha R et al (2006) Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion. Exp Neurol 198(2):285–293. https://doi.org/10.1016/j.expneurol.2005.08.030

    Article  CAS  PubMed  Google Scholar 

  33. Takeda A, Nakamura M, Fujii H, Tamano H (2013) Synaptic Zn2+ homeostasis and its significance. Metallomics 5(5):417–423. https://doi.org/10.1039/c3mt20269k

    Article  CAS  PubMed  Google Scholar 

  34. Krall RF, Tzounopoulos T, Aizenman E (2021) The function and regulation of zinc in the brain. Neuroscience 457:235–258. https://doi.org/10.1016/j.neuroscience.2021.01.010

    Article  CAS  PubMed  Google Scholar 

  35. Colvin RA, Bush AI, Volitakis I, Fontaine CP, Thomas D, Kikuchi K, Holmes WR (2008) Insights into Zn2+ homeostasis in neurons from experimental and modeling studies. Am J Physiol Cell Physiol 294(3):C726-742. https://doi.org/10.1152/ajpcell.00541.2007

    Article  CAS  PubMed  Google Scholar 

  36. Shuttleworth CW, Weiss JH (2011) Zinc: new clues to diverse roles in brain ischemia. Trends Pharmacol Sci 32(8):480–486. https://doi.org/10.1016/j.tips.2011.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Takeda A, Tamano H, Tempaku M, Sasaki M, Uematsu C, Sato S, Kanazawa H, Datki ZL et al (2017) Extracellular Zn2+ is essential for amyloid β1-42-induced cognitive decline in the normal brain and its rescue. J Neurosci 37(30):7253–7262. https://doi.org/10.1523/jneurosci.0954-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Takeda A, Koike Y, Osaw M, Tamano H (2018) Characteristic of extracellular Zn2+ influx in the middle-aged dentate gyrus and its involvement in attenuation of LTP. Mol Neurobiol 55(3):2185–2195. https://doi.org/10.1007/s12035-017-0472-z

    Article  CAS  PubMed  Google Scholar 

  39. Solomonov I, Korkotian E, Born B, Feldman Y, Bitler A, Rahimi F, Li H, Bitan G, Sagi I (2012) Zn2+-Aβ40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons. J Biol Chem 287(24):20555–20564. https://doi.org/10.1074/jbc.M112.344036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ji SG, Medvedeva YV, Wang HL, Yin HZ, Weiss JH (2019) Mitochondrial Zn2+ accumulation: a potential trigger of hippocampal ischemic injury. Neuroscientist 25(2):126–138. https://doi.org/10.1177/1073858418772548

    Article  CAS  PubMed  Google Scholar 

  41. Forostyak O, Forostyak S, Kortus S, Sykova E, Verkhratsky A, Dayanithi G (2016) Physiology of Ca2+ signalling in stem cells of different origins and differentiation stages. Cell Calcium 59(2–3):57–66. https://doi.org/10.1016/j.ceca.2016.02.001

    Article  CAS  PubMed  Google Scholar 

  42. Colbourne F, Grooms SY, Zukin RS, Buchan AM, Bennett MV (2003) Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia. Proc Natl Acad Sci USA 100(5):2906–2910. https://doi.org/10.1073/pnas.2628027100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stork CJ, Li YV (2009) Rising zinc: a significant cause of ischemic neuronal death in the CA1 region of rat hippocampus. J Cereb Blood Flow Metab 29(8):1399–1408. https://doi.org/10.1038/jcbfm.2009.64

    Article  CAS  PubMed  Google Scholar 

  44. Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME (2012) Zinc and human health: an update. Arch Toxicol 86(4):521–534. https://doi.org/10.1007/s00204-011-0775-1

    Article  CAS  PubMed  Google Scholar 

  45. Baltaci AK, Yuce K (2018) Zinc transporter proteins. Neurochem Res 43(3):517–530. https://doi.org/10.1007/s11064-017-2454-y

    Article  CAS  PubMed  Google Scholar 

  46. Baltaci AK, Yuce K, Mogulkoc R (2018) Zinc metabolism and metallothioneins. Biol Trace Elem Res 183(1):22–31. https://doi.org/10.1007/s12011-017-1119-7

    Article  CAS  PubMed  Google Scholar 

  47. Yu WH, Lukiw WJ, Bergeron C, Niznik HB, Fraser PE (2001) Metallothionein III is reduced in Alzheimer’s disease. Brain Res 894(1):37–45. https://doi.org/10.1016/s0006-8993(00)03196-6

    Article  CAS  PubMed  Google Scholar 

  48. Beyer N, Coulson DT, Heggarty S, Ravid R, Irvine GB, Hellemans J, Johnston JA (2009) ZnT3 mRNA levels are reduced in Alzheimer’s disease post-mortem brain. Mol Neurodegener 4:53. https://doi.org/10.1186/1750-1326-4-53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee SJ, Koh JY (2010) Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Molecular brain 3(1):30. https://doi.org/10.1186/1756-6606-3-30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Calvo-Rodriguez M, Bacskai BJ (2021) Mitochondria and calcium in Alzheimer’s disease: from cell signaling to neuronal cell death. Trends Neurosci 44(2):136–151. https://doi.org/10.1016/j.tins.2020.10.004

    Article  CAS  PubMed  Google Scholar 

  51. Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 90(2):567–571. https://doi.org/10.1073/pnas.90.2.567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ferreiro E, Oliveira CR, Pereira C (2004) Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J Neurosci Res 76(6):872–880. https://doi.org/10.1002/jnr.20135

    Article  CAS  PubMed  Google Scholar 

  53. Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimer’s Dis JAD 57(4):1041–1048. https://doi.org/10.3233/jad-160763

    Article  CAS  PubMed  Google Scholar 

  54. Navakkode S, Liu C, Soong TW (2018) Altered function of neuronal L-type calcium channels in ageing and neuroinflammation: Implications in age-related synaptic dysfunction and cognitive decline. Ageing Res Rev 42:86–99. https://doi.org/10.1016/j.arr.2018.01.001

    Article  CAS  PubMed  Google Scholar 

  55. Berger SM, Bartsch D (2014) The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. Cell Tissue Res 357(2):463–476. https://doi.org/10.1007/s00441-014-1936-3

    Article  CAS  PubMed  Google Scholar 

  56. Ritz B, Rhodes SL, Qian L, Schernhammer E, Olsen JH, Friis S (2010) L-type calcium channel blockers and Parkinson disease in Denmark. Ann Neurol 67(5):600–606. https://doi.org/10.1002/ana.21937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Webster NJ, Ramsden M, Boyle JP, Pearson HA, Peers C (2006) Amyloid peptides mediate hypoxic increase of L-type Ca2+ channels in central neurones. Neurobiol Aging 27(3):439–445. https://doi.org/10.1016/j.neurobiolaging.2005.02.002

    Article  CAS  PubMed  Google Scholar 

  58. Hotka M, Cagalinec M, Hilber K, Hool L, Boehm S, Kubista H (2020) L-type Ca(2+) channel-mediated Ca(2+) influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions. Sci Signal 13(618):eaaw6923(1-15). https://doi.org/10.1126/scisignal.aaw6923

  59. Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R et al (2002) The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Int Med 162(18):2046–2052. https://doi.org/10.1001/archinte.162.18.2046

    Article  Google Scholar 

  60. Pannicke T, Iandiev I, Uckermann O, Biedermann B, Kutzera F, Wiedemann P, Wolburg H, Reichenbach A et al (2004) A potassium channel-linked mechanism of glial cell swelling in the postischemic retina. Mol Cell Neurosci 26(4):493–502. https://doi.org/10.1016/j.mcn.2004.04.005

    Article  CAS  PubMed  Google Scholar 

  61. Jaffe DB, Ross WN, Lisman JE, Lasser-Ross N, Miyakawa H, Johnston D (1994) A model for dendritic Ca2+ accumulation in hippocampal pyramidal neurons based on fluorescence imaging measurements. J Neurophysiol 71(3):1065–1077. https://doi.org/10.1152/jn.1994.71.3.1065

    Article  CAS  PubMed  Google Scholar 

  62. Schulien AJ, Justice JA, Di Maio R, Wills ZP, Shah NH, Aizenman E (2016) Zn2+-induced Ca2+ release via ryanodine receptors triggers calcineurin-dependent redistribution of cortical neuronal Kv2.1 K+ channels. J Physiol 594(10):2647–2659. https://doi.org/10.1113/jp272117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Ann Rev Genet 39:359–407. https://doi.org/10.1146/annurev.genet.39.110304.095751

    Article  CAS  PubMed  Google Scholar 

  64. Malaiyandi LM, Vergun O, Dineley KE, Reynolds IJ (2005) Direct visualization of mitochondrial zinc accumulation reveals uniporter-dependent and -independent transport mechanisms. J Neurochem 93(5):1242–1250. https://doi.org/10.1111/j.1471-4159.2005.03116.x

    Article  CAS  PubMed  Google Scholar 

  65. Sensi SL, Paoletti P, Bush AI, Sekler I (2009) Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 10(11):780–791. https://doi.org/10.1038/nrn2734

    Article  CAS  PubMed  Google Scholar 

  66. Abramov AY, Canevari L, Duchen MR (2004) Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture. Biochem Biophys Acta 1742(1–3):81–87. https://doi.org/10.1016/j.bbamcr.2004.09.006

    Article  CAS  PubMed  Google Scholar 

  67. Angelova PR, Abramov AY (2014) Interaction of neurons and astrocytes underlies the mechanism of Aβ-induced neurotoxicity. Biochem Soc Trans 42(5):1286–1290. https://doi.org/10.1042/bst20140153

    Article  CAS  PubMed  Google Scholar 

  68. Görlach A, Bertram K, Hudecova S, Krizanova O (2015) Calcium and ROS: a mutual interplay. Redox Biol 6:260–271. https://doi.org/10.1016/j.redox.2015.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Colacurcio DJ, Nixon RA (2016) Disorders of lysosomal acidification-the emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75–88. https://doi.org/10.1016/j.arr.2016.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Seo BR, Lee SJ, Cho KS, Yoon YH, Koh JY (2015) The zinc ionophore clioquinol reverses autophagy arrest in chloroquine-treated ARPE-19 cells and in APP/mutant presenilin-1-transfected Chinese hamster ovary cells. Neurobiol Aging 36(12):3228–3238. https://doi.org/10.1016/j.neurobiolaging.2015.09.006

    Article  CAS  PubMed  Google Scholar 

  71. Zheng L, Kågedal K, Dehvari N, Benedikz E, Cowburn R, Marcusson J, Terman A (2009) Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis. Free Radical Biol Med 46(3):422–429. https://doi.org/10.1016/j.freeradbiomed.2008.10.043

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by grants from the National Natural Science Foundation of China (31272317), the National Nature Science Youth Foundation of China (81801076), the Natural Science Foundation of Tianjin City (20JCYBJC01370), Natural Science Foundation of Tianjin City (15JCYBJC24500), the Tianjin Natural Science Youth Foundation (18JCQNJC11400), the Fundamental Research Funds for the Central Universities of Nankai University (BE123081), and the Natural Science Foundation of Hebei Province (C2020423055).

Author information

Authors and Affiliations

  1. College of Life Sciences, Nankai University, Tianjin, 300071, China

    Wen-bo Chen, Hong-gang Wang, Di An, Dan Sun, Tao Zhang, Wan-ge Lu & Yan-qiang Liu

  2. School of Basic Medical Science, Henan University, Kaifeng, 475004, China

    Wen-bo Chen

  3. Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Hebei University of Chinese Medicine, Shijiazhuang, 050200, Hebei, China

    Yu-xiang Wang

  4. Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgery Institute, Department of Neurology, Tianjin Huanhu Hospital Affiliated to Nankai University, Tianjin, China

    Pan Li

Authors
  1. Wen-bo Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-xiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong-gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Di An
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wan-ge Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yan-qiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.B.C. designed and performed the experiments, analyzed the experimental data, prepared all figures, and wrote the manuscript. Y.Q.L. conceived the study, reviewed and revised the manuscript. The other authors help to perform the experiments, collect experimental data, review and revise the manuscript, and apply the funds. All the authors reviewed the manuscript.

Corresponding author

Correspondence to Yan-qiang Liu.

Ethics declarations

Ethics Approval and Consent to Participate

All procedures were compliant with the approved protocol from the Animal Ethics Committee of Nankai University and the Chinese animal welfare act and the “Chinese code of practice and use of animals for scientific purposes.”

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

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

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

Chen, Wb., Wang, Yx., Wang, Hg. et al. Role of TPEN in Amyloid-β25–35-Induced Neuronal Damage Correlating with Recovery of Intracellular Zn2+ and Intracellular Ca2+ Overloading. Mol Neurobiol 60, 4232–4245 (2023). https://doi.org/10.1007/s12035-023-03322-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03322-x

Keywords

Search

Navigation