Several epidemiological studies suggest the involvement of aluminum (AI) in the pathogenesis of Alzheimer's disease (AD). There is an increase in the levels of Aβ and ubiquitin in the pathological lesions of AD. Therefore, we have investigated whether aluminum (AI) treatment alters the levels of Aβ and ubiquitin in murine neuroblastoma (NBP2) and rat glioma (C-6) cell cultures. At a low concentration (10 μM), aluminum sulfate stimulated the level of immunoreactive Aβ and ubiquitin in NBP2 cells without changing the levels of the amyloid precursor protein (APP). However, at higher concentrations (100 and 500 μM), aluminum failed to elicit any significant effect on β-amylold, whereas ubiquitin levels continued to increase. No changes in the Aβ and ubiquitin content were found in the C-6 glioma cells following treatment with AI at any of the concentrations tested. Exposure of cells to aluminum salts did not alter the rate of proliferation in either of the two cell lines. These data suggest that one of the mechanisms by which AI may play a role in AD is by promoting the formation of Aβ and ubiquitin in neurons.
References
1.
CrapperDR, KrishnanSS, DaltonAJ. Brain aluminum distribution in Alzheimer's disease and experimental neurofibrillary degeneration. Science180: 511–513, 1973.
2.
MartynCN, BarkerDJP, OsmondC, HarrisEC, EdwardsonJA, LacyRF. Geographic relation between Alzheimer's disease and aluminum in drinking water. Lancet1: 59–62, 1989.
3.
RatenTP. Geographical associations between aluminum in drinking water and death rate with dementia (including Alzheimer's disease), Parkinson's disease, and amyotrophic lateral sclerosis in Norway. Environ Geochem Health12: 152–167, 1990.
4.
McLachlanDRC, BergeronC, SmithJE, BoomerD, RifatSL. Risk for neuropathologically confirmed Alzheimer's disease and residual aluminum in municipal drinking water employing weighted residential histories. Neurology46: 401–405, 1996.
5.
PerlDP, BrodyAR. Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science208: 297–299, 1980.
6.
McDermottJR, SmithAI, IqbalK, WisniewskiHM. Brain aluminum in aging and Alzheimer's disease. Neurology29: 809–814, 1979.
7.
BjertnessE, CandyJM, TorvikA, InceP, McArthurF, TaylorGA, JohansenSW, AlexanderJ, GronnesbyJK, BakketeigLS, EdwardsonJA. Content of brain aluminum is not elevated in Alzheimer disease. Alzheimer Dis Assoc Disord10: 171–174, 1996.
8.
PotterH, MaJ, DasS, KayyaliU.The involvement of amyloid associated proteins in the formation of β-protein filaments in Alzheimer's disease. In: FischbachGD, HirokawaN, HymanSE, OzawaT Eds. Molecular Neurobiology: Mechanisms Common to Brain, Skin, and Immune System. New York: Wiley-Liss Inc., pp 57–71, 1994.
9.
JoachinCL, SelkoeDJ. The seminal role of β-amyloid in the pathogenesis of Alzheimer's disease. Alzheimer Dis Assoc Disord46: 395–403, 1996.
10.
YankerBA, MesulamMM. β-Amyloid and pathogenesis of Alzheimer's disease. New Engl J Med325: 1849–1857, 1991.
11.
KudoT, IqbalK, RavidR, SwabbDF, Grandke-IqbalI.Alzheimer's disease: Correlation of cerebrospinal fluid and brain ubiquitin levels. Brain Res639: 1–7, 1994.
12.
WangGP, KhatoonS, IqbalK, Grandke-IqbalI.Brain ubiquitin is markedly elevated in Alzheimer's disease. Brain Res566: 146–151, 1991.
13.
AdamsFS, La RosaFG, KumarS, Edwards-PrasadJ, KentrotiS, VernadakisA, FreedCR, PrasadKN. Characterization and transplantation of two neuronal cell lines with dopaminergic properties. Neurochem Res21: 619–627, 1996.
14.
BendaP, LightbodyJ, SatoG, LevineL, SweetW.Differentiated rat glial cell strain in tissue culture. Science161: 370–371, 1968.
15.
La RosaFG, KumarS, PrasadKN. Increased expression of ubiquitin during adenosine 3′,5′-cyclic monophosphate-induced differentiation of neuroblastoma cells in culture. J Neurochem66: 1845–1850, 1996.
16.
BanksWA, ManessLM, BanksMF, KastenAJ. Aluminum-sensitive degradation of amyloid β-protein 1—40 by murine and human intracellular enzymes. Neurotoxicol Teratol18: 671–677, 1996.
17.
NeillD, LeakeD, HughesAB, KeithGA, TaylorGA, AllsopD, RimaBK, MorrisC, CandyJM, EdwardsonJA. Effect of aluminum on expression and processing of amyloid precursor protein. J Neurosci Res46: 395–403, 1996.
18.
MantyhPW, GhilardiJR, RogersS, DeMasterE, AllenCJ, StimsonER, MaggioJE. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of β-amyloid peptide. J Neurochem61: 1171–1174, 1993.
19.
KawaharaM, MuramotoK, KobayashiK, MoriH, KurodaY.Aluminum promotes the aggregation of Alzheimer's amyloid β-protein in vitro.Biochem Biophys Res Commun198: 531–535, 1994.
20.
BondySC, TruongA.Potentiation of beta-folding of β-amyloid peptide 25–35 by aluminum salts. Neurosci Lett267: 25–28, 1999.
21.
HochstrasserM.Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol7: 215–223, 1995.
22.
PrasadKN, La RosaFG, PrasadJE. Prostaglandins act as neurotoxin for differentiated neuroblastoma cells in culture and increase levels of ubiquitin and β-amyloid. In Vitro Cell Dev Biol Anim34: 265–274, 1998.
23.
CampbellA, PrasadKN, BondySC. Aluminum-induced oxidative events in cell lines: Glioma are more responsive than neuroblastoma. Free Radic Biol Med26: 1166–1171, 1999.
24.
ShinRW, LeeVMY, TrojanowskiJQ. Neurofibrillary pathology and aluminum in Alzheimer's disease. Histol Histopathol10: 969–978, 1995.
25.
ShinRW, LeeVM, TrojanowskiJQ. Aluminum modifies the properties of Alzheimer's disease PHFT proteins in vivo and in vitro.J Neurosci14: 7221–7233, 1994.
