Among the many factors responsible for the cognitive decline in Alzheimer's disease, beta amyloid protein and plaque formation is crucial. This amyloid pathology is associated with activation of glial cells and oxidative stress but whether oxidative stress activates beta amyloid protein in the neurons is not clear. Further the expression of microglia is also known to vary during pathogenesis of beta amyloid plaques. The aim of the present study is to evaluate the antioxidant effect of NAC on amyloid pathology and cognition and also to investigate the link between amyloid pathology and glial cells activation. Intracerebroventricular colchicine in rats known mimics human AD in many aspects including memory loss, oxidative stress, and hyper phosphorylation of tau protein. The animal groups consisted of age matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in active avoidance test; beta amyloid protein, beta amyloid plaques, astrocytes, and microglia cells were quantified using immunohistochemistry in hippocampal and prefrontal cortices. Colchicine has resulted in significant cognitive loss, increased intraneuronal beta amyloid protein expression, increased reactive astrocytes, and activated microglia in all the regions of the hippocampus and prefrontal cortices. The antioxidant NAC has reversed the cognitive deficits and inhibited microglia activation but failed to inhibit BAP expression and astrocytosis. Intraneuronal BAP accumulation is deleterious and known to adversely affect cognition, but in this study in spite of intraneuronal BAP accumulation, the cognition is restored. It can be postulated that NAC might have reversed the effect of intraneuronal beta amyloid protein by acting on some downstream compensatory mechanisms which needs to be explored.
Bloom G. S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurology. 2014;71(4):505–508. doi: 10.1001/jamaneurol.2013.5847. - DOI - PubMed
Alavi Naini S. M., Soussi-Yanicostas N. Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxidative Medicine and Cellular Longevity. 2015;2015:17. doi: 10.1155/2015/151979.151979 - DOI - PMC - PubMed
Cancelli I., Beltrame M., D'Anna L., Gigli G. L., Valente M. Drugs with anticholinergic properties: A potential risk factor for psychosis onset in Alzheimer's disease? Expert Opinion on Drug Safety. 2009;8(5):549–557. doi: 10.1517/14740330903099636. - DOI - PubMed
Terry R. D. Cell death or synaptic loss in Alzheimer disease. Journal of Neuropathology & Experimental Neurology. 2000;59(12):1118–1119. doi: 10.1093/jnen/59.12.1118. - DOI - PubMed
Wang S., et al. Is beta-amyloid accumulation a cause or consequence of alzheimer's disease? Journal of Alzheimer's Parkinsonism & Dementia. 2016;1(2) - PMC - PubMed
Zhao J., O'Connor T., Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis. Journal of Neuroinflammation. 2011;8, article 150(1) doi: 10.1186/1742-2094-8-150. - DOI - PMC - PubMed
Orre M., Kamphuis W., Osborn L. M., et al. Isolation of glia from Alzheimer's mice reveals inflammation anddysfunction. Neurobiology of Aging. 2014;35(12):2746–2760. doi: 10.1016/j.neurobiolaging.2014.06.004. - DOI - PubMed
Olabarria M., Noristani H. N., Verkhratsky A., Rodríguez J. J. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia. 2010;58(7):831–838. doi: 10.1002/glia.20967. - DOI - PubMed
Butterfield D. A., Lauderback C. M. Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid β-peptide-associated free radical oxidative stress. Free Radical Biology & Medicine. 2002;32(11):1050–1060. doi: 10.1016/S0891-5849(02)00794-3. - DOI - PubMed
Cheignon C., Tomas M., Bonnefont-Rousselot D., Faller P., Hureau C., Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biology. 2017;14:450–464. doi: 10.1016/j.redox.2017.10.014. - DOI - PMC - PubMed
Blasko I., Veerhuis R., Stampfer-Kountchev M., Saurwein-Teissl M., Eikelenboom P., Grubeck-Loebenstein B. Costimulatory effects of interferon-γ and interleukin-1β or tumor necrosis factor α on the synthesis of Aβ1-40 and Aβ1-42 by human astrocytes. Neurobiology of Disease. 2000;7(6):682–689. doi: 10.1006/nbdi.2000.0321. - DOI - PubMed
Coric V., et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Archives of Neurology. 2012;69(11):1430–1440. - PubMed
Huang W., Zhang X., Chen W. Role of oxidative stress in Alzheimer's disease. Biomedical Reports. 2016;4(5):519–522. doi: 10.3892/br.2016.630. - DOI - PMC - PubMed
Ono K., Hamaguchi T., Naiki H., Yamada M. Anti-amyloidogenic effects of antioxidants: implications for the prevention and therapeutics of Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2006;1762(6):575–586. doi: 10.1016/j.bbadis.2006.03.002. - DOI - PubMed
Cho C. G., Kim H. J., Chung S. W., et al. Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process. Experimental Gerontology. 2003;38(5):539–548. doi: 10.1016/S0531-5565(03)00005-6. - DOI - PubMed
Payne J. A., Reckelhoff J. F., Khalil R. A. Role of oxidative stress in age-related reduction of NO-cGMP-mediated vascular relaxation in SHR. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2003;285(3):R542–R551. doi: 10.1152/ajpregu.00056.2003. - DOI - PubMed
Adams J. D., Klaidman L. K., Odunze I. N., Shen H. C., Miller C. A. Alzheimer's and Parkinson's disease. Molecular and Chemical Neuropathology. 1991;14(3):213–226. doi: 10.1007/BF03159937. - DOI - PubMed
Sen O., Caner H., Aydin M. V., et al. The effect of mexiletine on the level of lipid peroxidation and apoptosis of endothelium following experimental subarachnoid hemorrhage. Neurological Research. 2006;28(8):859–863. doi: 10.1179/016164106X115099. - DOI - PubMed
Medved I., Brown M. J., Bjorksten A. R., Leppik J. A., Sostaric S., McKenna M. J. N-acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans. Journal of Applied Physiology. 2003;94(4):1572–1582. doi: 10.1152/japplphysiol.00884.2002. - DOI - PubMed
Tucker S., Ahl M., Cho H.-H., et al. RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine. Current Alzheimer Research. 2006;3(3):221–227. doi: 10.2174/156720506777632835. - DOI - PubMed
Luccarini I., Grossi C., Traini C., Fiorentini A., Ed Dami T., Casamenti F. Aβ plaque-associated glial reaction as a determinant of apoptotic neuronal death and cortical gliogenesis: A study in APP mutant mice. Neuroscience Letters. 2012;506(1):94–99. doi: 10.1016/j.neulet.2011.10.056. - DOI - PubMed
He N., et al. Amyloid-ß 142 oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death & Disease. 2013;4(11):p. e924. - PMC - PubMed
Chen Z., Zhong C. Oxidative stress in Alzheimer's disease. Neuroscience Bulletin. 2014;30(2):271–281. doi: 10.1007/s12264-013-1423-y. - DOI - PMC - PubMed
Xu P.-X., Wang S.-W., Yu X.-L., et al. Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation. Behavioural Brain Research. 2014;264:173–180. doi: 10.1016/j.bbr.2014.02.002. - DOI - PubMed
Dahl D., Bignami A., Bich N. T., Chi N. H. Immunohistochemical characterization of neurofibrillary tangles induced by mitotic spindle inhibitors. Acta Neuropathologica. 1980;51(2):165–168. doi: 10.1007/BF00690460. - DOI - PubMed
Shigematsu K., McGeer P. L. Accumulation of amyloid precursor protein in damaged neuronal processes and microglia following intracerebral administration of aluminum salts. Brain Research. 1992;593(1):117–123. doi: 10.1016/0006-8993(92)91272-G. - DOI - PubMed
Kumar M. H. V., Gupta Y. K. Intracerebroventricular administration of colchicine produces cognitive impairment associated with oxidative stress in rats. Pharmacology Biochemistry & Behavior. 2002;73(3):565–571. doi: 10.1016/s0091-3057(02)00838-9. - DOI - PubMed
Nakayama T., Sawada T. Involvement of microtubule integrity in memory impairment caused by colchicine. Pharmacology Biochemistry & Behavior. 2002;71(1-2):119–138. doi: 10.1016/S0091-3057(01)00634-7. - DOI - PubMed
Madhyastha S., Somayaji S. N., Rao M. S., Nalini K., Bairy K. L. Hippocampal brain amines in methotrexate-induced learning and memory deficit. Canadian Journal of Physiology and Pharmacology. 2002;80(11):1076–1084. doi: 10.1139/y02-135. - DOI - PubMed
Pelligrino L. J., Pelligrino A. S., et al. A Stereotaxic Atlas of the Rat Brain. 2nd. New York, NY, USA: Plenum Press; 1981.
Watson G. P. A. C. The Rat Brain in Stereotaxic Coordinates. 7th. Academic Press; 2013. edition.
Farr S. A., Poon H. F., Dogrukol-Ak D., et al. The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. Journal of Neurochemistry. 2003;84(5):1173–1183. doi: 10.1046/j.1471-4159.2003.01580.x. - DOI - PubMed
Shi J.-Q., Shen W., Chen J., et al. Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Research. 2011;1368:239–247. doi: 10.1016/j.brainres.2010.10.053. - DOI - PubMed
Wang Q., Xu J., Rottinghaus G. E. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Research. 2002;958(2):439–447. doi: 10.1016/S0006-8993(02)03543-6. - DOI - PubMed
Leon W. C., Canneva F., Partridge V., et al. A novel transgenic rat model with a full alzheimer's - Like amyloid pathology displays pre - Plaque intracellular amyloid -β- Associated cognitive impairment. Journal of Alzheimer's Disease. 2010;20(1):113–126. doi: 10.3233/JAD-2010-1349. - DOI - PubMed
Sil S., et al. A comparison of neurodegeneration linked with neuroinflammation in different brain areas of rats after intracerebroventricular colchicine injection. Journal of Immunotoxicology. 2016;13(2):181–190. - PubMed
Sil S., Goswami A. R., Dutta G., Ghosh T. Effects of naproxen on immune responses in a colchicine-induced rat model of Alzheimer's disease. Neuroimmunomodulation. 2014;21(6):304–321. doi: 10.1159/000357735. - DOI - PubMed
Kumar A., Dogra S., Prakash A. Neuroprotective effects of Centella asiatica against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress. International Journal of Alzheimer's Disease. 2009;2009:8. doi: 10.4061/2009/972178.972178 - DOI - PMC - PubMed
Khurana S., Jain S., Mediratta P. K., Banerjee B. D., Sharma K. K. Protective role of curcumin on colchicine-induced cognitive dysfunction and oxidative stress in rats. Human & Experimental Toxicology. 2012;31(7):686–697. doi: 10.1177/0960327111433897. - DOI - PubMed
Raghavendra M., et al. Role of aqueous extract of Azadirachta indica leaves in an experimental model of Alzheimer's disease in rats. International Journal of Applied and Basic Medical Research. 2013;3(1):p. 37. - PMC - PubMed
Cantuti-Castelvetri I., Shukitt-Hale B., Joseph J. A. Neurobehavioral aspects of antioxidants in aging. International Journal of Developmental Neuroscience. 2000;18(4-5):367–381. doi: 10.1016/S0736-5748(00)00008-3. - DOI - PubMed
Eakin K., et al. Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One. 2014;9(4)e90617 - PMC - PubMed
Khan M., Sekhon B., Jatana M. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. Journal of Neuroscience Research. 2004;76(4):519–527. doi: 10.1002/jnr.20087. - DOI - PubMed
Moussawi K., Pacchioni A., Moran M., et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nature Neuroscience. 2009;12(2):182–189. doi: 10.1038/nn.2250. - DOI - PMC - PubMed
Fu A.-L., Dong Z.-H., Sun M.-J. Protective effect of N-acetyl-l-cysteine on amyloid β-peptide-induced learning and memory deficits in mice. Brain Research. 2006;1109(1):201–206. doi: 10.1016/j.brainres.2006.06.042. - DOI - PubMed
Studer R., Baysang G., Brack C. N-Acetyl-L-Cystein downregulates β-amyloid precursor protein gene transcription in human neuroblastoma cells. Biogerontology. 2001;2(1):55–60. doi: 10.1023/A:1010065103073. - DOI - PubMed
Qin W., Ho L., Pompl P. N., et al. Cyclooxygenase (COX)-2 and COX-1 potentiate β-amyloid peptide generation through mechanisms that involve γ-secretase activity. The Journal of Biological Chemistry. 2003;278(51):50970–50977. doi: 10.1074/jbc.M307699200. - DOI - PubMed
Stuchbury G., Münch G. Alzheimer's associated inflammation, potential drug targets and future therapies. Journal of Neural Transmission. 2005;112(3):429–453. doi: 10.1007/s00702-004-0188-x. - DOI - PubMed
Nagele R. G., D'Andrea M. R., Lee H., Venkataraman V., Wang H.-Y. Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Research. 2003;971(2):197–209. doi: 10.1016/S0006-8993(03)02361-8. - DOI - PubMed
Rodríguez J. J., Olabarria M., Chvatal A., Verkhratsky A. Astroglia in dementia and Alzheimer's disease. Cell Death & Differentiation. 2009;16(3):378–385. doi: 10.1038/cdd.2008.172. - DOI - PubMed
Hertz L., Peng L., Dienel G. A. Energy metabolism in astrocytes: High rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. Journal of Cerebral Blood Flow & Metabolism. 2007;27(2):219–249. doi: 10.1038/sj.jcbfm.9600343. - DOI - PubMed
González-Reyes R. E., Nava-Mesa M. O., Vargas-Sánchez K., Ariza-Salamanca D., Mora-Muñoz L. Involvement of astrocytes in Alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Frontiers in Molecular Neuroscience. 2017;10:p. 247.
Abramov A. Y., Canevari L., Duchen M. R. Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2004;1742(1-3):81–87. doi: 10.1016/j.bbamcr.2004.09.006. - DOI - PubMed
Joy T., Rao M., Madhyastha S. N-acetyl cysteine supplement minimize tau expression and neuronal loss in animal model of alzheimer’s disease. Brain Sciences. 2018;8(10):p. 185. doi: 10.3390/brainsci8100185. - DOI - PMC - PubMed
Ingelsson M., Fukumoto H., Newell K. L., et al. Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62(6):925–931. doi: 10.1212/01.wnl.0000115115.98960.37. - DOI - PubMed
Perez-Nievas B. G., Stein T. D., Tai H., et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain. 2013;136(8):2510–2526. doi: 10.1093/brain/awt171. - DOI - PMC - PubMed
Bryan K. J., Lee H., Perry G., et al. Transgenic mouse models of Alzheimer’s disease: behavioral testing and considerations. In: Buccafusco J. J., editor. Methods of Behavior Analysis in Neuroscience. 2nd. Boca Raton (FL): CRC Press/Taylor & Francis; 2009.
Kametani F., Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer's disease. Frontiers in Neuroscience. 2018;12:p. 25. - PMC - PubMed
Gandhi S., Abramov A. Y. Mechanism of oxidative stress in neurodegeneration. Oxidative Medicine and Cellular Longevity. 2012;2012:11. doi: 10.1155/2012/428010.428010 - DOI - PMC - PubMed
Tchantchou F., Graves M., Rogers E., Ortiz D., Shea T. B. N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency. Journal of Alzheimer's Disease. 2005;7(2):135–138. doi: 10.3233/JAD-2005-7206. - DOI - PubMed
Kettenmann H., Hanisch U. K., Noda M., Verkhratsky A. Physiology of microglia. Physiological Reviews. 2011;91(2):461–553. doi: 10.1152/physrev.00011.2010. - DOI - PubMed
Gold M., El Khoury J. Seminars in Immunopathology. Vol. 37. Springer; 2015. β-amyloid, microglia, and the inflammasome in Alzheimer’s disease; pp. 607–611. - DOI - PMC - PubMed
Aoyama K., Suh W. S., Hamby A. M., et al. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nature Neuroscience. 2006;9(1):119–126. doi: 10.1038/nn1609. - DOI - PubMed
Kerksick C., Willoughby D. The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. Journal of the International Society of Sports Nutrition. 2005;2(2):38–44. doi: 10.1186/1550-2783-2-2-38. - DOI - PMC - PubMed
Reddy P. H. Amyloid precursor protein-mediated free radicals and oxidative damage: Implications for the development and progression of Alzheimer's disease. Journal of Neurochemistry. 2006;96(1):1–13. - PubMed
Karalija A., Novikova L. N., Kingham P. J., Wiberg M., Novikov L. N. Neuroprotective effects of N-acetyl-cysteine and acetyl-L-carnitine after spinal cord injury in adult rats. PLoS ONE. 2012;7(7) doi: 10.1371/journal.pone.0041086.e41086 - DOI - PMC - PubMed