Abstract
Repetitive transcranial magnetic stimulation (rTMS) is a technique protecting neurons against diverse neurodegenerative disorders by delivering magnetic stimuli into the brain through the intact scalp. In the current study, the protection effect of rTMS on Parkinson’s disease (PD) and the associated mechanism driving the treatment were explored. The PD symptoms were induced using 6-OHDA in mice, and the effect of rTMS of two frequencies (1 Hz and 10 Hz) on the cognitive behaviors and neuron viability was detected. Afterwards, the level of Aβ1–42 and activity of MKK7-ERK-Fos-APP axis under the administration of rTMS were recorded as well. The intracranial injection of 6-OHDA impaired the cognitive behaviors of the mice in the test of Morris water maze as well as reducing the viability and number of neurons in PD mice. After the treatment of rTMS of both frequencies, the cognitive function of mice was improved and the neuron viability and number were restored in mice brain tissues. The administration of rTMS also increased the cerebrospinal fluid (CSF) level of Aβ1–42 in PD mice, which was accompanied by the suppressed levels of p-MKK7, p-ERK1/2, p–c-Fos, and APP. Moreover, the effect of rTMS on mice nerve system was all exerted in a frequency-dependent manner. In conclusion, the findings outlined in the current study affirmed the protection effect of rTMS against PD. The anti-PD function of rTMS was associated with the suppression of MKK7-ERK-Fos-APP axis, which subsequently resulted in the increased CSF Aβ1–42 level and decreased brain Aβ1–42 level.
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References
Driver JA, Logroscino G, Gaziano JM, Kurth T (2009) Incidence and remaining lifetime risk of Parkinson disease in advanced age. Neurology 72(5):432–438. https://doi.org/10.1212/01.wnl.0000341769.50075.bb
Buchman AS, Shulman JM, Nag S, Leurgans SE, Arnold SE, Morris MC, Schneider JA, Bennett DA (2012) Nigral pathology and parkinsonian signs in elders without Parkinson’s disease. Ann Neurol 71(2):258–266
Lees AJ, Hardy J, Revesz T (2004) Parkinson’s disease. Lancet 363(Suppl):1783–1793
Marras C, Lang A (2013) Parkinson’s disease subtypes: lost in translation? J Neurol Neurosur Ps 84(4):409–415. https://doi.org/10.1136/jnnp-2012-303455
van Dijk KD, Teunissen CE, Drukarch B, Jimenez CR, Groenewegen HJ, Berendse HW, van de Berg WD (2010) Diagnostic cerebrospinal fluid biomarkers for Parkinson’s disease: a pathogenetically based approach. Neurobiol Dis 39(3):229–241. https://doi.org/10.1016/j.nbd.2010.04.020
Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9(11):1044–1045
Nyhlén J, Constantinescu R, Zetterberg H (2010) Problems associated with fluid biomarkers for Parkinson’s disease. Biomarkers Med 4(5):671–681
Parnetti L, Castrioto A, Chiasserini D, Persichetti E, Tambasco N, El-Agnaf O, Calabresi P (2013) Cerebrospinal fluid biomarkers in Parkinson disease. Nat Rev Neurol 9(3):131–140
Bekris LM, Tsuang DW, Peskind ER, Yu CE, Montine TJ, Zhang J, Zabetian CP, Leverenz JB (2015) Cerebrospinal fluid Aβ42 levels and APP processing pathway genes in Parkinson’s disease. Movement Disord 30(7):936–944
Zetterberg H, Lunn MP, Herukka SK (2012) Clinical use of cerebrospinal fluid biomarkers in Alzheimer’s disease. Biomarkers Med 6(4):371–376
Postina R (2008) A closer look at alpha-secretase. Curr Alzheimer Res 5(2):179–186
Deuss M, Reiss K, Hartmann D (2008) Part-time alpha-secretases: the functional biology of ADAM 9, 10 and 17. Curr Alzheimer Res 5:2
Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113(10):1456
Colciaghi F, Borroni B, Pastorino L, Marcello E, Zimmermann M, Cattabeni F, Padovani A, Di LM (2002) [alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients. Mo Med 8(2):67
Qin W, Ho L, Wang J, Peskind E, Pasinetti GM (2009) S100A7, a novel Alzheimer’s disease biomarker with non-amyloidogenic alpha-secretase activity acts via selective promotion of ADAM-10. PLoS ONE 4(1):e4183
Zetterberg H, Andreasson U, Hansson O, Wu G, Sankaranarayanan S, Andersson ME, Buchhave P, Londos E, Umek RM, Minthon L (2008) Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol-Chicago 65(8):1102–1107
Wu G, Sankaranarayanan S, Tugusheva K, Kahana J, Seabrook G, Shi XP, King E, Devanarayan V, Cook JJ, Simon AJ (2008) Decrease in age-adjusted cerebrospinal fluid beta-secretase activity in Alzheimer’s subjects. Clin Biochem 41(12):986–996
Ewers M, Zhong Z, Bürger K, Wallin A, Blennow K, Teipel SJ, Shen Y, Hampel H (2008) Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer’s disease. Brain 131(5):1252–1258
Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S (2005) Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J 19(7):739–749
Stockley JH, O’Neill C (2007) The proteins BACE1 and BACE2 and beta-secretase activity in normal and Alzheimer’s disease brain. Biochem Soc Trans 35(3):574–576
Zhang J (2002) aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 3(1):85–97
Baulac S, Lavoie MJ, Kimberly WT, Strahle J, Wolfe MS, Selkoe DJ, Xia W (2003) Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates. Neurobiol Dis 14(2):194–204
Kimberly WT, Lavoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ (2003) γ-secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and Pen-2. Proc Natl Acad Sci USA 100(11):6382–6387
Gersner R, Kravetz E, Feil J, Pell G, Zangen A (2011) Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals. J Neurosci 31(20):7521–7526
Wang HY, Crupi D, Liu J, Stucky A, Cruciata G, Di RA, Friedman E, Quartarone A, Ghilardi MF (2011) Repetitive transcranial magnetic stimulation enhances BDNF-TrkB signaling in both brain and lymphocyte. J Neurosci 31(30):11044–11054
Miranda PC, Lomarev M, Hallett M (2006) Modeling the current distribution during transcranial direct current stimulation. Clin Neurophysio 117(7):1623–1629
Fregni F, Simon D, Wu A, Pascual-Leone A (2005) Non-invasive brain stimulation for Parkinson’s disease: a systematic review and meta-analysis of the literature. J Neurol Neurosur Psychiatry 76(12):1614
Tan T, Xie J, Liu T, Chen X, Zheng X, Tong Z, Tian X (2013) Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) reverses Aβ(1–42)-mediated memory deficits in rats. Exp Gerontol 48(8):786–794
Huang YA, Zhou B, Wernig M, Südhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate app transcription and Aβ secretion. Cell 168(3):427
Ridding MC, Rothwell JC (2007) Is there a future for therapeutic use of transcranial magnetic stimulation? Nat Rev Neurosci 8(7):559–567
Ni Z, Chen R (2015) Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases. Transl Neurodegener 4(1):22
Oscar AC (2008) Basic mechanisms of rTMS: implications in Parkinson’s disease. Int Arch Med 1(1):2
Colaianna M, Tucci P, Zotti M, Morgese MG, Schiavone S, Govoni S, Cuomo V, Trabace L (2010) Soluble βamyloid1–42: a critical player in producing behavioural and biochemical changes evoking depressive-related state? Br J Pharmacol 159(8):1704
Holsinger RM, Schnarr J, Henry P, Castelo VT, Fahnestock M (2000) Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer’s disease. Mol Brain Res 76(2):347–354
Parnetti L, Chiasserini D, Bellomo G, Giannandrea D, De CC, Qureshi MM, Ardah MT, Varghese S, Bonanni L, Borroni B (2011) Cerebrospinal fluid Tau/α-synuclein ratio in Parkinson’s disease and degenerative dementias. Mov Disord 26(8):1428–1435
Elahi B, Chen R (2010) Effect of transcranial magnetic stimulation on Parkinson motor function–systematic review of controlled clinical trials. Mov Disord 24(3):357–363
Zanjani A, Zakzanis KK, Daskalakis ZJ, Chen R (2015) Repetitive transcranial magnetic stimulation of the primary motor cortex in the treatment of motor signs in Parkinson’s disease: a quantitative review of the literature. Mov Disord 30(6):750–758
Nielsen NS, Jacobsen C (1997) Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48(5):1398–1403
Wagleshukla A, Angel MJ, Zadikoff C, Enjati M, Gunraj C, Lang AE, Chen R (2007) Low-frequency repetitive transcranial magnetic stimulation for treatment of levodopa-induced dyskinesias. Neurology 68(9):704–705
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11010_2019_3531_MOESM1_ESM.tif
Supplementary material 1 (TIFF 83 kb) Figure S1. Schematic diagram of the experiment schedule. 10-week old mice were intracranially injected with 2 μl 6-OHDA (4 μg/μl) and housed routinely for 2 weeks before rTMS treatment of 2 weeks.
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Ba, F., Zhou, Y., Zhou, J. et al. Repetitive transcranial magnetic stimulation protects mice against 6-OHDA-induced Parkinson’s disease symptoms by regulating brain amyloid β1–42 level. Mol Cell Biochem 458, 71–78 (2019). https://doi.org/10.1007/s11010-019-03531-w
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DOI: https://doi.org/10.1007/s11010-019-03531-w