- Open Access
- Open Peer Review
Why nutraceuticals do not prevent or treat Alzheimer's disease
© Fisher and Naughton; licensee BioMed Central Ltd. 2005
- Received: 23 November 2004
- Accepted: 12 April 2005
- Published: 12 April 2005
A great deal of research has pointed to deleterious roles of metal ions in the development of Alzheimer's disease. These include: i) the precipitation and aggregation of amyloid β (Aβ) peptides to form senile plaques and neurofibrillary tangles, and/or ii) the augmentation of oxidative stress by metal ion mediated production and activation of hydrogen peroxide. The growing trend in nutraceutical intake is in part a result of the belief that they postpone the development of dementias such as Alzheimer's disease. However, pathogenic events centred on metal ions are expected to be aggravated by frequent nutraceutical intake. Novel therapeutic approaches centred on chelators with specificity for copper and iron ions should be fully explored.
- Neurofibrillary Tangle
- Senile Plaque
- High Affinity Binding Site
Dementia currently affects over 750,000 people in the UK, with Alzheimer's disease (AD) accounting for 55 % of those cases. As a result of increasing life expectancy, the number of people predicted to suffer from dementia is expected to rise to over 1.8 million by 2050. Currently there are no known cures for AD. Existing treatments at best only delay the progression of disease and accurate diagnosis can only be made with certainty at autopsy. Hence, there is an urgent need for new therapeutic approaches and for reliable and noninvasive methods to aid in the early diagnosis of AD and to give an indication of disease progression. Advanced AD is evident from the apparent progressive decline in cognitive function as a result of loss of neurons. These are accompanied by pathological changes including extracellular amyloid β plaques and intracellular changes called neurofibrillary tangles, which are abnormal deposits of hyperphosphorylated tau proteins .
Recent reports ascribe a major role for the metal ions, iron, copper and zinc in AD. Specifically the redox active metal ions Fe2+ and Cu+ can generate the highly reactive and oxidizing species, the hydroxyl radical via the Fenton reaction. This species is thought to account for a large proportion of oxidative modifications that are seen in AD brains including lipid peroxidation, nucleic acid oxidation and protein carbonylation. Also metal ions have been shown to be central to Aβ pathogenicity.
The Aβ peptide is a low molecular weight protein consisting of 39–43 amino acids. It has two high affinity binding sites, one specific for copper and one specific for zinc. In the Aβ1–42 peptide (the predominant Aβ species found in amyloid plaques in AD brains) the high affinity binding site binds Cu2+ were estimated at log K = 17.2 and 16.3 at pH 7.4 and pH 6.6 respectively, and the low affinity binding site at log K = 8.3 and 7.5 at pH 7.4 and 6.6 respectively . At physiological pH values, soluble Aβ is precipitated by Zn2+ in vitro. However, at pH levels reflecting physiological acidosis, which is characteristic of AD, in vitro precipitation of Aβ is induced by cupric and ferric ions. Cupric ions induce greater precipitation than ferric ions, which is thought to be a result of its higher binding affinity, with Aβ aggregation enhanced to ~85 % . In addition, Cu2+ ions are bound at the low affinity site completely displacing the Zn2+ ions in physiological acidosis . Levels of copper, iron and zinc have been analyzed in the rims and cores of senile plaques of AD patients and concentrations were found to be highly elevated. Concentrations exhibited in the senile plaques cores were 22.7 ± 6.5, 52.4 ± 14.5 and 67.0 ± 13.0 μg/g for copper, iron and zinc respectively . In addition serum copper levels have been shown to be markedly elevated in AD .
The catalytic effects of transition metals on the formation of reactive oxygen species are becoming evident as a major factor in AD. Aβ binds to Cu2+ reducing it to Cu+. The Aβ-Cu+ complex can then trap dioxygen and reduce it to hydrogen peroxide (H2O2). One study demonstrated that 1 μM Cu2+ when bound to Aβ could catalytically generate 10 μM H2O2, indicating continual redox cycling . In conditions where this reaction is not favorable, biological reducing agents such as vitamin C have been shown to enhance this reaction . The generation of H2O2 has been shown to be neurotoxic, which is considered to be a result of its reduction to the hydroxyl radical via Fenton chemistry. Cupric ion binding is dependent on histidine and tyrosine amino acid residues. Upon generation of hydroxyl radicals localized to the Cu2+ ion, the tyrosine residues can cross-link to form dityrosine. This further stabilizes the Aβ plaques conferring resistance to proteolysis . Further studies are required to establish if Aβ bound to Cu2+ and Zn2+ exhibits significant anti-oxidant enzyme activities (superoxide dismutase and catalase activities) in vivo, as many researchers have likened Aβ to the native CuZn superoxide dismutase enzyme in both its conformation and its metal binding affinities .
Magnetite and maghemite deposits have been found in brains of patients suffering from AD and studies are underway to correlate enhanced levels with disease progression . However, magnetite detection is only possible after the onset of AD. A comprehensive understanding of the levels and nature of redox-active ferric ions is warranted to assess the mechanisms of magnetite deposition. AD brains exhibit increased levels of oxidatively modified nucleic acids, specifically RNA in vulnerable neurons . Haem oxygenase-1 (HO-1), an enzyme which catalyses the breakdown of haem to biliverdin with release of iron and carbon monoxide, is over-expressed in the brains of AD patients. So it could be postulated that this would be one source of redox-active iron. Immunostaining of neurons demonstrated that HO-1 expression was co-localized to the neurofibrillary tangles . However oxidative damage to nucleic acids was reduced in neurons exhibiting neurofibrillary tangles demonstrating an antioxidant mechanism for HO-1 and an involvement in tau proteins expression. Further studies on the oxidative modifications of RNA in AD demonstrated it to be localized to iron rich lysosomes called lipofuscins originating from the mitochondria. This indicates a disruption in mitochondrial function leading to accumulation of redox-active iron in the neuronal cytoplasm  and subsequent reactive oxygen species generation.
Oxidative stress is one of the key mechanisms of neurotoxicity in AD, and studies have shown that Aβ neurotoxicity can be partially or completely attenuated by the antioxidant enzyme catalase [6, 7]. Plasma levels of antioxidants including vitamin E, uric acid and vitamin C are depleted in AD patients . Therefore, many people have proposed the supplementation of antioxidants such as vitamin E and vitamin C. Several studies have reported that increased intake either through diet or supplementation results in reduced incidence of AD [15–17]. However, other studies do not report such success . In fact, some studies have shown that vitamin C which can also act as a pro-oxidant can also induce neuronal oxidative stress via its interaction with metal ions .
A long-term imbalance in metal ion homeostasis is rarely treatable by alterations in diet. Therefore, research is focusing on the development of new methods for therapeutic intervention, specifically chelators to remove the deleterious metal ions, with concomitant dissolution of the Aβ plaques. In vitro studies on the aggregation of Aβ induced by metal ions, showed that this was completely reversible by metal ion chelation . As a result of these observations new chelators are being developed as novel therapies for AD, however many are restricted by their poor target specificity. Clioquinol a Cu/Zn chelator was tested in APP2576 transgenic mice and appeared to selectively bind the Aβ-metal complex resulting in dissolution of Aβ plaques, reducing brain Aβ by 49 % . No neurotoxicity was exhibited. Clioquinol subsequently was tested in a clinical trial with 36 AD patients. It affected a rise in plasma concentrations of zinc, and also decreased plasma concentrations of Aβ 1–42 . However more studies are required to determine its importance in treating AD. Many other metal ion chelators are currently under investigation for treatment of AD [22–25].
We have developed a series of metal ion chelators for both the study and treatment of metal deposition disorders. These include the development of the first-ever, reactive oxygen and nitrogen species probe for the simultaneous detection of multiple RONS and the role of redox-active metal ions in their generation and suppression . Alteration of the basic structure of these probes affords anti-oxidant enzyme mimics . In addition the chelator EGTA, which has previously been shown to dissolve Aβ plaques  was also demonstrated to have substantial superoxide dismutase activity when complexed to redox-active metal ions . Thus, addition of a chelator that generates a superoxide dismutase or catalase mimic could 'dissolve' the magnetite deposits and Aβ plaques and negate oxidative damage arising from them.
Metal specific chelators afford a major opportunity for the control of metal ion mediated pathogeneses, which is not currently provided by nutraceuticals. In particular, administration of "prodrug" chelators that mimic anti-oxidant enzymes with high specificity for Cu2+ and Fe3+ ions will: i) counteract oxidative stress, ii) help to control metal ion deposition and iii) dissolve Aβ plaques and, maghemite and magnetite residues.
We are grateful to the University of Brighton and the Engineering and Physical Sciences Research Council for financial support.
- Luchsinger JA, Mayeux R: Dietary factors and Alzheimer's disease. Lancet Neurol. 2004, 3: 579-587. 10.1016/S1474-4422(04)00878-6.View ArticlePubMedGoogle Scholar
- Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI: Characterization of copper interactions with Alzheimer amyloid β peptides: identification of an attomolar-affinity copper binding site on amyloid β1–42. J Neurochem. 2000, 75: 1219-1233. 10.1046/j.1471-4159.2000.0751219.x.View ArticlePubMedGoogle Scholar
- Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI: Dramatic Aggregation of Alzheimer Abeta by Cu(II) Is Induced by Conditions Representing Physiological Acidosis. J Biol Chem. 1998, 273: 12817-12826. 10.1074/jbc.273.21.12817.View ArticlePubMedGoogle Scholar
- Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR: Copper, iron and zinc in Alzheimer's disease senile plaques. J Neurol Sci. 1998, 158: 47-52. 10.1016/S0022-510X(98)00092-6.View ArticlePubMedGoogle Scholar
- Squitti R, Lupoi D, Pasqualetti P, Dal Forno G, Vernieri F, Chiovenda P, Rossi L, Cortesi M, Cassetta E, Rossini PM: Elevation of serum copper levels in Alzheimer's disease. Neurology. 2002, 59: 1153-1161.View ArticlePubMedGoogle Scholar
- Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, et al: Cu(II) potentiation of alzheimer Abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999, 274: 37111-37116. 10.1074/jbc.274.52.37111.View ArticlePubMedGoogle Scholar
- Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, et al: Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J Biol Chem. 2002, 277: 40302-40308. 10.1074/jbc.M206428200.View ArticlePubMedGoogle Scholar
- Atwood CS, Perry G, Zeng H, Kato Y, Jones WD, Ling KQ, Huang X, Moir RD, Wang D, Sayre LM, et al: Copper mediates dityrosine cross-linking of Alzheimer's amyloid-beta. Biochemistry. 2004, 43: 560-568. 10.1021/bi0358824.View ArticlePubMedGoogle Scholar
- Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ: Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem. 2001, 276: 20466-20473. 10.1074/jbc.M100175200.View ArticlePubMedGoogle Scholar
- Dobson J: Nanoscale biogenic iron oxides and neurodegenerative disease. FEBS Lett. 2001, 496: 1-5. 10.1016/S0014-5793(01)02386-9.View ArticlePubMedGoogle Scholar
- Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA: RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999, 19: 1959-1964.PubMedGoogle Scholar
- Schipper HM: Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med. 2004, 37: 1995-2011. 10.1016/j.freeradbiomed.2004.09.015.View ArticlePubMedGoogle Scholar
- Perry G, Nunomura A, Hirai K, Zhu X, Prez M, Avila J, Castellani RJ, Atwood CS, Aliev G, Sayre LM: Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases?. Free Radic Biol Med. 2002, 33: 1475-1479. 10.1016/S0891-5849(02)01113-9.View ArticlePubMedGoogle Scholar
- Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, Catani M, Cecchetti R, Senin U, Mecocci P, et al: Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiol Aging. 2003, 24: 915-919. 10.1016/S0197-4580(03)00031-9.View ArticlePubMedGoogle Scholar
- Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C, Muller-Thomsen T, Beisiegel U: Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease. Free Radic Biol Med. 2001, 31: 345-354. 10.1016/S0891-5849(01)00595-0.View ArticlePubMedGoogle Scholar
- Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JCM, Breteler MMB: Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. 2002, 287: 3223-3229. 10.1001/jama.287.24.3223.View ArticlePubMedGoogle Scholar
- Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA: Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. J Am Med Assoc. 2002, 287: 3230-3237. 10.1001/jama.287.24.3230.View ArticleGoogle Scholar
- Luchsinger JA, Tang MX, Shea S, Mayeux R: Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol. 2003, 60: 203-208. 10.1001/archneur.60.2.203.View ArticlePubMedGoogle Scholar
- White AR, Barnham KJ, Huang X, Voltakis I, Beyreuther K, Masters CL, Cherny RA, Bush AI, Cappai R: Iron inhibits neurotoxicity induced by trace copper and biological reductants. J Biol Inorg Chem. 2004, 9: 269-280. 10.1007/s00775-004-0521-8.View ArticlePubMedGoogle Scholar
- Bush AI: Metal complexing agents as therapies for Alzheimer's disease. Neurobiol Aging. 2002, 23: 1031-1038. 10.1016/S0197-4580(02)00120-3.View ArticlePubMedGoogle Scholar
- Doraiswamy PM, Finefrock AE: Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol. 2004, 3: 431-434. 10.1016/S1474-4422(04)00809-9.View ArticlePubMedGoogle Scholar
- Cherny RA, Barnham KJ, Lynch T, Volitakis I, Li QX, McLean CA, Multhaup G, Beyreuther K, Tanzi RE, Masters CL, Bush AI: Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease. J Struct Biol. 2000, 130: 209-216. 10.1006/jsbi.2000.4285.View ArticlePubMedGoogle Scholar
- Dedeoglu A, Cormier K, Payton S, Tseitlin KA, Kremsky JN, Lai L, Li X, Moir RD, Tanzi RE, Bush AI: Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis. Exp Gerontol. 2004, 39: 1641-1649. 10.1016/j.exger.2004.08.016.View ArticlePubMedGoogle Scholar
- Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik ZI, Warshawsky A, Youdim MBH, Fridkin M: Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorg Med Chem. 2004Google Scholar
- Lee JY, Friedman JE, Angel I, Kozak A, Koh JY: The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein transgenic mice. Neurobiol Aging. 2004, 25: 1315-1321. 10.1016/j.neurobiolaging.2004.01.005.View ArticlePubMedGoogle Scholar
- Fisher AEO, Naughton DP: Novel peptoids for the detection and suppression of reactive oxygen and nitrogen species. Biochem Soc Trans. 2003, 31: 1302-1304.View ArticlePubMedGoogle Scholar
- Fisher AEO, Maxwell SC, Naughton DP: Catalase and superoxide dismutase mimics for the treatment of inflammatory diseases. Inorg Chem Comm. 2003, 6: 1205-1208. 10.1016/S1387-7003(03)00223-5.View ArticleGoogle Scholar
- Maskos Z, Rush JD, Koppenol WH: The hydroxylation of tryptophan. Arch Biochem Biophys. 1992, 296: 514-520. 10.1016/0003-9861(92)90605-V.View ArticlePubMedGoogle Scholar
- Fisher AEO, Hague TA, Clarke CL, Naughton DP: Catalytic superoxide scavenging by metal complexes of the calcium chelator EGTA and contrast agent EHPG. Biochem Biophys Res Comm. 2004, 323: 163-167. 10.1016/j.bbrc.2004.08.066.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.