PDF herunterladen
CC BY-NC-ND 4.0 · Arq Neuropsiquiatr 2016; 74(09): 737-744
DOI: 10.1590/0004-282X20160121
ARTICLES

Aged Lewis rats exposed to low and moderate doses of rotenone are a good model for studying the process of protein aggregation and its effects upon central nervous system cell physiology

Ratos Lewis idosos expostos a baixa e moderada doses de rotenona são um bom modelo para estudar o processo de agregação proteica e seus efeitos sobre a fisiologia celular do sistema nervoso central
Michael F. Almeida
1   Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, São Paulo SP, Brasil.
,
Carolliny M. Silva
1   Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, São Paulo SP, Brasil.
,
Aline M. D’Unhao
1   Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, São Paulo SP, Brasil.
,
Merari F. R. Ferrari
1   Universidade de São Paulo, Instituto de Biociências, Departamento de Genética e Biologia Evolutiva, São Paulo SP, Brasil.
› InstitutsangabenSupport: This study was supported by research grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (2013/08028-1; 2015/18961-2) and Conselho Nacional de desenvolvimento Cientifico e Tecnologico (CNPq) (471999/2013-0; 401670/2013-9). M.F.A and C.M.S. received fellowships from FAPESP; A.M.D. received fellowship from CNPq.
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

ABSTRACT

Cell physiology is impaired before protein aggregation and this may be more relevant than inclusions themselves for neurodegeneration. The present study aimed to characterize an animal model to enable the analysis of the cell biology before and after protein aggregation. Ten-month-old Lewis rats were exposed either to 1 or 2 mg/kg/day of rotenone, delivered subcutaneously through mini-pumps, for one month. Hyperphosphorylated TAU, alpha-synuclein, amyloid-beta peptide and protein carbonylation (indicative of oxidative stress) were evaluated in the hippocampus, substantia nigra and locus coeruleus through immunohistochemistry or western blot. It was found that 2 mg/kg/day rotenone increased amyloid-beta peptide, hyperphosphorylation of TAU and alpha-synuclein. Rotenone at 1mg/kg/day did not alter protein levels. Protein carbonylation remained unchanged. This study demonstrated that aged Lewis rats exposed to a low dose of rotenone is a useful model to study cellular processes before protein aggregation, while the higher dose makes a good model to study the effects of protein inclusions.

RESUMO

A fisiologia celular está prejudicada antes da agregação proteica podendo ser mais importante para a neurodegeneração do que as próprias inclusões. Assim, o objetivo deste estudo é caracterizar um modelo animal para analisar os mecanismos e efeitos da agregação proteica. Ratos Lewis com 10 meses de idade foram expostos a rotenona (1 ou 2 mg/kg/dia), administrada subcutaneamente, utilizando minibombas osmóticas. Os níveis de peptídeo beta-amiloide, TAU hiperfosforilada, alfa-sinucleína e proteínas carboniladas (indicativo de estresse oxidativo) foram avaliados por imunohistoquímica e western blot no hipocampo, substância negra e locus coeruleus. Foi demonstrado que 2 mg/kg/dia de rotenona promoveu aumento do peptídeo beta-amiloide, hiperfosforilação da TAU e alfa-sinucleína. Já 1 mg/kg/dia de rotenona não alterou os níveis dessas proteína nessas regiões. As proteínas carboniladas não se alteraram. Foi demonstrado que ratos Lewis idosos expostos a baixas doses de rotenona são modelo de estudo dos processos celulares antes da agregação proteica, enquanto 2 mg/kg/dia de rotenona permite estudos sobre os efeitos da agregação proteica.

protein aggregates - rats - neurodegeneration
agregados proteicos - ratos - neurodegeneração

Support:

Support: This study was supported by research grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) (2013/08028-1; 2015/18961-2) and Conselho Nacional de desenvolvimento Cientifico e Tecnologico (CNPq) (471999/2013-0; 401670/2013-9). M.F.A and C.M.S. received fellowships from FAPESP; A.M.D. received fellowship from CNPq.




Publikationsverlauf

Eingereicht: 04. Januar 2016

Angenommen: 08. Juni 2016

Artikel online veröffentlicht:
06. September 2023

© 2023. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 

  • References

  • 1 Kalache A, Gatti A. Active ageing: a policy framework. Adv Gerontol. 2003;11:7-18.
  • 2 Ferrer I. Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog Neurobiol. 2012;97(1):38-51. doi:10.1016/j.pneurobio.2012.03.005
  • 3 Taipa R, Pinho J, Melo-Pires M. Clinico-pathological correlations of the most common neurodegenerative dementias. Front Neurol. 2012;3:68. doi:10.3389/fneur.2012.00068
  • 4 Halliday GM, Holton JL, Revesz T, Dickson DW. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122(2):187-204. doi:10.1007/s00401-011-0852-9
  • 5 Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010;68(6):1067-81. doi:10.1016/j.neuron.2010.11.030
  • 6 Riemer J, Kins S. Axonal transport and mitochondrial dysfunction in Alzheimer’s disease. Neurodegener Dis. 2013;12(3):11-24. doi:10.1159/000342020
  • 7 Xie W, Chung KK. Alpha-synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson’s disease. J Neurochem. 2012;122(2):404-14. doi:10.1111/j.1471-4159.2012.07769.x
  • 8 Melo TQ, D’unhao AM, Martins SA, Farizatto KL, Chaves RS, Ferrari MF. Rotenone-dependent changes of anterograde motor protein expression and mitochondrial mobility in brain areas related to neurodegenerative diseases. Cell Mol Neurobiol. 2013;33(3):327-35. doi:10.1007/s10571-012-9898-z
  • 9 Tang Y, Scott DA, Das U, Edland SD, Radomski K, Koo EH et al. Early and selective impairments in axonal transport kinetics of synaptic cargoes induced by soluble amyloid beta-protein oligomers. Traffic. 2012;13(5):681-93. doi:10.1111/j.1600-0854.2012.01340.x
  • 10 Heras-Sandoval D, Ferrera P, Arias C. Amyloid-β protein modulates insulin signaling in presynaptic terminals. Neurochem Res. 2012;37(9):1879-85. doi:10.1007/s11064-012-0800-7
  • 11 Gaugler MN, Genc O, Bobela W, Mohanna S, Ardah MT, El-Agnaf OM et al. Nigrostriatal overabundance of alpha-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity. Acta Neuropathol. 2012;123(5):653-69. doi:10.1007/s00401-012-0963-y
  • 12 Fang C, Bourdette D, Banker G. Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases. Mol Neurodegener. 2012;7(1):29. doi:10.1186/1750-1326-7-29
  • 13 Umeda T, Tomiyama T, Sakama N, Tanaka S, Lambert MP, Klein WL et al. Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. J Neurosci Res. 2011;89(7):1031-42. doi:10.1002/jnr.22640
  • 14 Stadtman ER, Berlett BS. Reactive oxygen-mediated protein oxidation in aging and disease. Drug Metab Rev 1998;30(2):225-43. doi:10.3109/03602539808996310
  • 15 Xiong N, Long X, Xiong J, Jia M, Chen C, Huang J et al. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Crit Rev Toxicol. 2012;42(7):613-32. doi:10.3109/10408444.2012.680431
  • 16 Chaves RS, Melo TQ, Martins SA, Ferrari MF. Protein aggregation containing β -amyloid, α-synuclein and hyperphosphorylated τ in cultured cells of hippocampus, substantia nigra and locus coeruleus after rotenone exposure. BMC Neurosci. 2010;11(1):144. doi:10.1186/1471-2202-11-144
  • 17 Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol. 2012;2012:845618. doi:10.1155/2012/845618
  • 18 Isaacs AM, Senn DB, Yuan M, Shine JP, Yankner BA. Acceleration of amyloid beta-peptide aggregation by physiological concentrations of calcium. J Biol Chem. 2006;28 (38):27916-23. doi:10.1074/jbc.M602061200
  • 19 Leuner K, Schutt T, Kurz C, Eckert SH, Schiller C, Occhipinti A et al. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signaling. 2012;16(12):1421-33. doi:10.1089/ars.2011.4173
  • 20 Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron. 2011;70(3):410-26. doi:10.1016/j.neuron.2011.04.009
  • 21 Höglinger GU, Lannuzel A, Khondiker ME, Michel PP, Duyckaerts C, Féger J et al. The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy. J Neurochem. 2005;95(4):930-9. doi:10.1111/j.1471-4159.2005.03493.x
  • 22 Fleming SM, Zhu C, Fernagut PO, Mehta A, DiCarlo CD, Seaman RL et al. () Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp Neurol. 2004;187(2):418-29. doi:10.1016/j.expneurol.2004.01.023
  • 23 Sherer TB, Kim JH, Betarbet R, Greenamyre JT. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol. 2003;179 (1):9-16. doi:10.1006/exnr.2002.8072
  • 24 Alam M, Schmidt WJ. Mitochondrial complex I inhibition depletes plasma testosterone in the rotenone model of Parkinson’s disease. Physiol Behav. 2004;83(3):395-400. doi:10.1016/j.physbeh.2004.08.010
  • 25 Melo TQ, D’Unhao A M, Martins SA, Farizatto KL, Chaves RS, Ferrari MF. Rotenone-dependent changes of anterograde motor protein expression and mitochondrial mobility in brain areas related to neurodegenerative diseases. Cell Mol Neurobiol. 2013;33(3):327-35. doi:10.1007/s10571-012-9898-z
  • 26 Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA. 2011;108(10):4194-9. doi:10.1073/pnas.1100976108
  • 27 Leuner K, Hauptmann S, Abdel-Kader R, Scherping I, Keil U, Strosznajder JB. Mitochondrial dysfunction: the first domino in brain aging and Alzheimer’’s disease? Antioxid Redox Signal. 2007;9(10):1659-75. doi:10.1089/ars.2007.1763
  • 28 Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A. Protein carbonylation in human diseases. Trends Mol Med. 2003;9(4):169-76. doi:10.1016/S1471-4914(03)00031-5