Oxidative stress in Alzheimer's disease: why did antioxidant therapy fail?

Torbjörn Persson, Bogdan O Popescu, Angel Cedazo-Minguez, Torbjörn Persson, Bogdan O Popescu, Angel Cedazo-Minguez

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet. A remarkable amount of data supports the hypothesis that oxidative stress is an early and important pathogenic operator in AD. However, all clinical studies conducted to date did not prove a clear beneficial effect of antioxidant treatment in AD patients. In the current work, we review the current knowledge about oxidative stress in AD pathogeny and we suggest future paths that are worth to be explored in animal models and clinical studies, in order to get a better approach of oxidative imbalance in this inexorable neurodegenerative disease.

References

    1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer's and Dementia. 2013;9, article e2:63–75.
    1. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiological Reviews. 2001;81(2):741–766.
    1. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Journal of the American Medical Association. 1997;278(16):1349–1356.
    1. Wenk GL. Neuropathologic changes in Alzheimer’s disease. Journal of Clinical Psychiatry. 2003;64(supplement 9):7–10.
    1. Stadelmann C, Deckwerth TL, Srinivasan A, et al. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease: evidence for apoptotic cell death. The American Journal of Pathology. 1999;155(5):1459–1466.
    1. Albrecht S, Bogdanovic N, Ghetti B, Winblad B, Leblanc AC. Caspase-6 activation in familial Alzheimer disease brains carrying amyloid precursor protein or presenilin i or presenilin II mutations. Journal of Neuropathology and Experimental Neurology. 2009;68(12):1282–1293.
    1. Selkoe DJ. The deposition of amyloid proteins in the aging mammalian brain: implications for Alzheimer’s disease. Annals of Medicine. 1989;21(2):73–76.
    1. Grundke-Iqbal I, Iqbal K, Quinlan M. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. Journal of Biological Chemistry. 1986;261(13):6084–6089.
    1. Xiang Z, Haroutunian V, Ho L, Purohit D, Pasinetti GM. Microglia activation in the brain as inflammatory biomarker of Alzheimer’s disease neuropathology and clinical dementia. Disease Markers. 2006;22(1-2):95–102.
    1. Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. Journal of Neuropathology and Experimental Neurology. 2001;60(8):759–767.
    1. Koopman WJ, Nijtmans LG, Dieteren CE, et al. Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation. Antioxidants and Redox Signaling. 2010;12(12):1431–1470.
    1. Doorn JA, Petersen DR. Covalent adduction of nucleophilic amino acids by 4-hydroxynonenal and 4-oxononenal. Chemico-Biological Interactions. 2003;143-144:93–100.
    1. Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cellular and Molecular Life Sciences. 2007;64(17):2202–2210.
    1. Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2′-deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. Journal of Environmental Science and Health C. 2009;27(2):120–139.
    1. Poulsen HE, Specht E, Broedbaek K, et al. RNA modifications by oxidation: a novel disease mechanism? Free Radical Biology and Medicine. 2012;52(8):1353–1361.
    1. Ding Q, Markesbery WR, Chen Q, Li F, Keller JN. Ribosome dysfunction is an early event in Alzheimer’s disease. Journal of Neuroscience. 2005;25(40):9171–9175.
    1. Milne GL, Musiek ES, Morrow JD. F2-isoprostanes as markers of oxidative stress in vivo: an overview. Biomarkers. 2005;10(supplement 1):S10–S23.
    1. Liu T, Stern A, Roberts LJ, Morrow JD. The isoprostanes: novel prostaglandin-like products of the free radical- catalyzed peroxidation of arachidonic acid. Journal of Biomedical Science. 1999;6(4):226–235.
    1. Headlam HA, Davies MJ. Markers of protein oxidation: different oxidants give rise to variable yields of bound and released carbonyl products. Free Radical Biology and Medicine. 2004;36(9):1175–1184.
    1. Alderson NL, Wang Y, Blatnik M, et al. S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Archives of Biochemistry and Biophysics. 2006;450(1):1–8.
    1. Zeng J, Davies MJ. Evidence for the formation of adducts and S-(carboxymethyl)cysteine on reaction of α-dicarbonyl compounds with thiol groups on amino acids, peptides, and proteins. Chemical Research in Toxicology. 2005;18(8):1232–1241.
    1. Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. Journal of Biological Chemistry. 1997;272(33):20313–20316.
    1. Ricci C, Pastukh V, Leonard J, et al. Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis. The American Journal of Physiology—Cell Physiology. 2008;294(2):C413–C422.
    1. Saitoh M, Nishitoh H, Fujii M, et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO Journal. 1998;17(9):2596–2606.
    1. Nadeau PJ, Charette SJ, Toledano MB, Landry J. Disulfide bond-mediated multimerization of Ask1 and its reduction by thioredoxin-1 regulate H2O2-induced c-Jun NH2-terminal kinase activation and apoptosis. Molecular Biology of the Cell. 2007;18(10):3903–3913.
    1. Yamamoto H, Ozaki T, Nakanishi M, et al. Oxidative stress induces p53-dependent apoptosis in hepatoblastoma cell through its nuclear translocation. Genes to Cells. 2007;12(4):461–471.
    1. Bradley MA, Xiong-Fister S, Markesbery WR, Lovell MA. Elevated 4-hydroxyhexenal in Alzheimer’s disease (AD) progression. Neurobiology of Aging. 2012;33(6):1034–1044.
    1. Markesbery WR, Kryscio RJ, Lovell MA, Morrow JD. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Annals of Neurology. 2005;58(5):730–735.
    1. Praticò D, Lee VM, Trojanowski JQ, Rokach J, Fitzgerald GA. Increased F2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid peroxidation in vivo. The FASEB Journal. 1998;12(15):1777–1783.
    1. Lovell MA, Xie C, Markesbery WR. Acrolein is increased in Alzheimer’s disease brain and is toxic to primary hippocampal cultures. Neurobiology of Aging. 2001;22(2):187–194.
    1. Kuhla B, Haase C, Flach K, Lüth H-J, Arendt T, Münch G. Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation. Journal of Biological Chemistry. 2007;282(10):6984–6991.
    1. Lovell MA, Soman S, Bradley MA. Oxidatively modified nucleic acids in preclinical Alzheimer’s disease (PCAD) brain. Mechanisms of Ageing and Development. 2011;132(8-9):443–448.
    1. Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Annals of Neurology. 1994;36(5):747–751.
    1. Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s disease. Journal of Neurochemistry. 2005;93(4):953–962.
    1. Hensley K, Hall N, Subramaniam R, et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. Journal of Neurochemistry. 1995;65(5):2146–2156.
    1. Ansari MA, Scheff SW. Oxidative stress in the progression of alzheimer disease in the frontal cortex. Journal of Neuropathology and Experimental Neurology. 2010;69(2):155–167.
    1. Montine TJ, Beal MF, Cudkowicz ME, et al. Increased CSF F2-isoprostane concentration in probable AD. Neurology. 1999;52(3):562–565.
    1. Lovell MA, Gabbita SP, Markesbery WR. Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. Journal of Neurochemistry. 1999;72(2):771–776.
    1. Ahmed N, Ahmed U, Thornalley PJ, Hager K, Fleischer G, Münch G. Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer’s disease and link to cognitive impairment. Journal of Neurochemistry. 2005;92(2):255–263.
    1. Greilberger J, Koidl C, Greilberger M, et al. Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer’s disease. Free Radical Research. 2008;42(7):633–638.
    1. Sinem F, Dildar K, Gökhan E, Melda B, Orhan Y, Filiz M. The serum protein and lipid oxidation marker levels in Alzheimer’s disease and effects of cholinesterase inhibitors and antipsychotic drugs therapy. Current Alzheimer Research. 2010;7(5):463–469.
    1. Irizarry MC, Yao Y, Hyman BT, Growdon JH, Praticò D. Plasma F2A isoprostane levels in Alzheimer’s and Parkinson’s disease. Neurodegenerative Diseases. 2007;4(6):403–405.
    1. Montine TJ, Quinn JF, Milatovic D, et al. Peripheral F2-isoprostanes and F4-neuroprostanes are not increased in Alzheimer’s disease. Annals of Neurology. 2002;52(2):175–179.
    1. Kadioglu E, Sardas S, Aslan S, Isik E, Karakaya AE. Detection of oxidative DNA damage in lymphocytes of patients with Alzheimer’s disease. Biomarkers. 2004;9(2):203–209.
    1. Migliore L, Fontana I, Trippi F, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiology of Aging. 2005;26(5):567–573.
    1. Abe T, Tohgi H, Isobe C, Murata T, Sato C. Remarkable increase in the concentration of 8-hydroxyguanosine in cerebrospinal fluid from patients with Alzheimer’s disease. Journal of Neuroscience Research. 2002;70(3):447–450.
    1. Resende R, Moreira PI, Proença T, et al. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radical Biology and Medicine. 2008;44(12):2051–2057.
    1. Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metabolism. 2011;14(6):724–738.
    1. Marszalek JR, Lodish HF. Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you. Annual Review of Cell and Developmental Biology. 2005;21:633–657.
    1. Karuppagounder SS, Xu H, Shi Q, et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer’s mouse model. Neurobiology of Aging. 2009;30(10):1587–1600.
    1. Lustbader JW, Cirilli M, Lin C, et al. ABAD directly links Aβ to mitochondrial toxicity in Alzheimer’s disease. Science. 2004;304(5669):448–452.
    1. Takuma K, Yao J, Huang J, et al. ABAD enhances Aβ-induced cell stress via mitochondrial dysfunction. The FASEB Journal. 2005;19(6):597–598.
    1. Akterin S, Cowburn RF, Miranda-Vizuete A, et al. Involvement of glutaredoxin-1 and thioredoxin-1 in β-amyloid toxicity and Alzheimer’s disease. Cell Death and Differentiation. 2006;13(9):1454–1465.
    1. Cenini G, Sultana R, Memo M, Butterfield DA. Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE,in brain from subjects with amnestic mild cognitive impairment and Alzheimer’s disease. Journal of Cellular and Molecular Medicine. 2008;12(3):987–994.
    1. Sharma A, Sharma R, Chaudhary P, et al. 4-Hydroxynonenal induces p53-mediated apoptosis in retinal pigment epithelial cells. Archives of Biochemistry and Biophysics. 2008;480(2):85–94.
    1. Ramassamy C, Averill D, Beffert U, et al. Oxidative insults are associated with apolipoprotein E genotype in Alzheimer’s disease brain. Neurobiology of Disease. 2000;7(1):23–37.
    1. Glodzik-Sobanska L, Pirraglia E, Brys M, et al. The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer’s disease. Neurobiology of Aging. 2009;30(5):672–681.
    1. Miyata M, Smith JD. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides. Nature Genetics. 1996;14(1):55–61.
    1. Benzi G, Moretti A. Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system. Free Radical Biology and Medicine. 1995;19(1):77–101.
    1. Calabrese V, Sultana R, Scapagnini G, et al. Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer’s disease. Antioxidants and Redox Signaling. 2006;8(11-12):1975–1986.
    1. Sultana R, Piroddi M, Galli F, Butterfield DA. Protein levels and activity of some antioxidant enzymes in hippocampus of subjects with amnestic mild cognitive impairment. Neurochemical Research. 2008;33(12):2540–2546.
    1. Duffy SL, Lagopoulos J, Hickie IB, et al. Glutathione relates to neuropsychological functioning in mild cognitive impairment. Alzheimer's and Dement. 2013
    1. Puertas MC, Martínez-Martos JM, Cobo MP, Carrera MP, Mayas MD, Ramírez-Expósito MJ. Plasma oxidative stress parameters in men and women with early stage Alzheimer type dementia. Experimental Gerontology. 2012;47(8):625–630.
    1. Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiology of Aging. 2003;24(7):915–919.
    1. Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, Stefanescu C. Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neuroscience Letters. 2010;469(1):6–10.
    1. Berr C, Richard M-J, Gourlet V, Garrel C, Favier A. Enzymatic antioxidant balance and cognitive decline in aging—the EVA study. European Journal of Epidemiology. 2004;19(2):133–138.
    1. Loef M, Schrauzer GN, Walach H. Selenium and Alzheimer’s disease: a systematic review. Journal of Alzheimer’s Disease. 2011;26(1):81–104.
    1. Brigelius-Flohé R, Traber MG. Vitamin E: function and metabolism. The FASEB Journal. 1999;13(10):1145–1155.
    1. Baldeiras I, Santana I, Proença MT, et al. Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer’s disease. Journal of Alzheimer’s Disease. 2008;15(1):117–128.
    1. Mangialasche F, Xu W, Kivipelto M, et al. Tocopherols and tocotrienols plasma levels are associated with cognitive impairment. Neurobiology of Aging. 2012;33(10):2282–2290.
    1. Jiménez-Jiménez FJ, de Bustos F, Molina JA, et al. Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Alzheimer’s disease. Journal of Neural Transmission. 1997;104(6-7):703–710.
    1. Mangialasche F, Kivipelto M, Mecocci P, et al. High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age. Journal of Alzheimer’s Disease. 2010;20(4):1029–1037.
    1. von Arnim CA, Herbolsheimer F, Nikolaus T, et al. Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany. Journal of Alzheimer's Disease. 2012;31:717–724.
    1. Akbaraly NT, Hininger-Favier I, Carrière I, et al. Plasma selenium over time and cognitive decline in the elderly. Epidemiology. 2007;18(1):52–58.
    1. Schweizer U, Streckfuß F, Pelt P, et al. Hepatically derived selenoprotein P is a key factor for kidney but not for brain selenium supply. Biochemical Journal. 2005;386(2):221–226.
    1. Lovell MA, Xie CS, Gabbita SP, Markesbery WR. Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer’s disease brain. Free Radical Biology and Medicine. 2000;28(3):418–427.
    1. Gil-Bea F, Akterin S, Persson TR, et al. Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer's disease brain. EMBO Molecular Medicine. 2012;4(10):1097–1111.
    1. Pekkari K, Holmgren A. Truncated Thioredoxin: hysiological functions and mechanism. Antioxidants and Redox Signaling. 2004;6(1):53–61.
    1. Torres LL, Quaglio NB, de Souza GT, et al. Peripheral oxidative stress biomarkers in mild cognitive impairment and alzheimer’s disease. Journal of Alzheimer’s Disease. 2011;26(1):59–68.
    1. Tang M-X, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. The Lancet. 1996;348(9025):429–432.
    1. Schönknecht P, Pantel J, Klinga K, et al. Reduced cerebrospinal fluid estradiol levels are associated with increased β-amyloid levels in female patients with Alzheimer’s disease. Neuroscience Letters. 2001;307(2):122–124.
    1. Mateos L, Persson T, Katoozi S, Gil-Bea FJ, Cedazo-Minguez A. Estrogen protects against amyloid-beta toxicity by estrogen receptor alpha-mediated inhibition of Daxx translocation. Neuroscience Letters. 2012;506(2):245–250.
    1. Cedazo-Mínguez A, Cowburn RF. Apolipoprotein E isoform-specific disruption of phosphoinositide hydrolysis: protection by estrogen and glutathione. FEBS Letters. 2001;504(1-2):45–49.
    1. Arlt S, Müller-Thomsen T, Beisiegel U, Kontush A. Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer's disease. Neurochemical Research. 2012;37(12):2706–2714.
    1. Galasko DR, Peskind E, Clark CM, et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Archives of Neurology. 2012;69(7):836–841.
    1. Tolonen M, Halme M, Sarna S. Vitamin E and selenium supplementation in geriatric patients. Biological Trace Element Research. 1985;7(3):161–168.
    1. Kryscio RJ, Abner EL, Schmitt FA, et al. A randomized controlled Alzheimer's disease prevention trial's evolution into an exposure trial: the preadvise Trial. The journal of Nutrition, Health and Aging . 2013;17(1):72–75.
    1. Reddy AC, Lokesh BR. Studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes. Molecular and Cellular Biochemistry. 1992;111(1-2):117–124.
    1. Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s β-amyloid fibrils in vitro. Journal of Neuroscience Research. 2004;75(6):742–750.
    1. Begum AN, Jones MR, Lim GP, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. Journal of Pharmacology and Experimental Therapeutics. 2008;326(1):196–208.
    1. Ma Q-L, Yang F, Rosario ER, et al. β-Amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. Journal of Neuroscience. 2009;29(28):9078–9089.
    1. Baum L, Lam CWK, Cheung SK-K, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. Journal of Clinical Psychopharmacology. 2008;28(1):110–113.
    1. Ringman JM, Frautschy SA, Teng E, et al. Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimer's Research and Therapy. 2012;4(5):p. 43.
    1. Disilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutrition Journal. 2012;11, article 79
    1. Bridi R, Crossetti FP, Steffen VM, Henriques AT. The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytotherapy Research. 2001;15(5):449–451.
    1. Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults a randomized trial. Journal of the American Medical Association. 2009;302(24):2663–2670.
    1. Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. The Lancet Neurology. 2012;11(10):851–859.
    1. Chan A, Remington R, Kotyla E, Lepore A, Zemianek J, Shea TB. A Vitamin/nutriceutical formulation improves memory and cognitive performance in community-dwelling adults without dementia. Journal of Nutrition, Health and Aging. 2010;14(3):224–230.
    1. Dolatabadi HRD, Reisi P, Alaei H, Malekabadi HA, Pilehvarian AA. Folic acid and coenzyme Q10 ameliorate cognitive dysfunction in the rats with intracerebroventricular injection of streptozotocin. Iranian Journal of Basic Medical Sciences. 2012;15(2):719–724.
    1. Kwong LK, Kamzalov S, Rebrin I, et al. Effects of coenzyme Q10 administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat. Free Radical Biology and Medicine. 2002;33(5):627–638.
    1. Thal LJ, Grundman M, Berg J, et al. Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology. 2003;61(11):1498–1502.
    1. Lu C, Zhang D, Whiteman M, Armstrong JS. Is antioxidant potential of the mitochondrial targeted ubiquinone derivative MitoQ conserved in cells lacking mtDNA? Antioxidants and Redox Signaling. 2008;10(3):651–660.
    1. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. The Journal of the American Medical Association. 2000;283(8):1007–1015.
    1. Janusz M, Lisowski J. Proline-rich polypeptide (PRP)–an immunomodulatory peptide from ovine colostrum. Archivum Immunologiae et Therapiae Experimentalis. 1993;41(5-6):275–279.
    1. Boldogh I, Liebenthal D, Hughes TK, et al. Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum. Journal of Molecular Neuroscience. 2003;20(2):125–134.
    1. Zabłocka A, Janusz M. Effect of the proline-rich polypeptide complex/colostrininTM on the enzymatic antioxidant system. Archivum Immunologiae et Therapiae Experimentalis. 2012;60(5):383–390.
    1. Leszek J, Inglot AD, Janusz M, et al. Colostrinin proline-rich polypeptide complex from ovine colostrum—a long-term study of its efficacy in Alzheimer’s disease. Medical Science Monitor. 2002;8(10):PI93–PI96.
    1. Bilikiewicz A, Gaus W. Colostrinin1 (a naturally occuring, proline-rich, polypeptide mixture) in the treatment of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2004;6(1):17–26.
    1. Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid β- protein (Aβ) in human neuroblastoma cells. Biochemistry. 2000;39(23):6951–6959.
    1. Paola D, Domenicotti C, Nitti M, et al. Oxidative stress induces increase in intracellular amyloid β-protein production and selective activation of βI and βII PKCs in NT2 cells. Biochemical and Biophysical Research Communications. 2000;268(2):642–646.
    1. Shen C, Chen Y, Liu H, et al. Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase. Journal of Biological Chemistry. 2008;283(25):17721–17730.
    1. Terada A, Yoshida M, Seko Y, et al. Active oxygen species generation and cellular damage by additives of parenteral preparations: selenium and sulfhydryl compounds. Nutrition. 1999;15(9):651–655.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi