Neurol Sci DOI 10.1007/s10072-014-1668-x
REVIEW ARTICLE
Zinc and its effects on oxidative stress in Alzheimer’s disease Ye Yuan • Fenglan Niu • Ya Liu • Na Lu
Received: 22 October 2013 / Accepted: 29 January 2014 Ó Springer-Verlag Italia 2014
Abstract Alzheimer’s disease (AD) is a progressive agerelated neurodegenerative disorder. The patho-physiological characteristic of AD is abnormal deposition of fibrillar amyloid b protein, intracellular neurofibrillary tangles, oxidative damage and neuronal death in the brain. Zinc is an important trace element in human body regulating many physiological processes. Increasing evidence suggests that the etiology of AD may involve disruptions of zinc homeostasis, and oxidative stress facilitating reactive oxygen species production is an early and sustained event in AD disease progression. Both Zn deficiency and Zn overload may affect cellular Zn distribution and be linked to neurodegeneration in AD. Meanwhile, Zn may play paradoxical roles in initiating and inhibiting oxidative stress and neurotoxicity. This review will focus on aspects of the role of zinc in AD, which includes a large body of research regarding zinc dyshomeostasis and its relation with oxidative stress. Keywords Alzheimer’s disease Zinc Oxidative stress Neurodegeneration
Y. Yuan The Department of Anesthesiology, The First Bethune Hospital of Jilin University, Changchun, People’s Republic of China F. Niu Y. Liu The School of Public Health, Jilin University, Changchun, People’s Republic of China N. Lu (&) The Department of Pediatrics, The First Bethune Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun 130021, People’s Republic of China e-mail: [email protected]
Introduction Alzheimer’s disease (AD) is the most common dementia and accounts for an estimated 60–80 % of cases in Western societies. But the cause of progression and pathology of AD is not very clear. Different concepts of the etiology of AD exist including the ‘metal hypothesis’ which has attracted increasing attention in recent two decades [1]. The hypothesis focuses on the disease-associated alterations of metals in the brain which participate in the cascade of pathogenic events that finally cause the clinical symptoms. Metal ions play a key role in synaptic function and their homeostasis is tightly regulated. Among the important essential trace metals, zinc has a variety of functions in hundreds of enzymes and protein domains with different types of zinc finger motifs [2]. Our understanding of the roles played by zinc in the physiological and pathological functioning of the brain is rapidly increasing. Brain zinc accumulation is a prominent feature of advanced AD and is biochemically linked to brain amyloid b-peptide (Ab) accumulation and dementia severity in AD. So a breakdown in this metal homeostasis and the generation of toxic Ab oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Meanwhile, abnormal metal homeostasis may enhance the production of reactive oxygen species (ROS) and finally contribute to AD. A relationship exists between signs of oxidative stress and Ab accumulation in AD brain [3]. In this review, we summarize the knowledge of the physiological role of zinc, zinc dyshomeostasis, and its effects on oxidative stress in AD.
Physiological role of zinc in the brain Zinc is one of the most important trace elements in human body which is essential for many physiological processes
123
Neurol Sci
such as cell proliferation and differentiation, growth and development, and enzymatic activity regulation. Zn is also involved in hormonal storage and release, neurotransmission and memory [4], acting similar to calcium as a second messenger, so zinc is also called ‘‘the calcium of the twenty-first century’’ [5]. Another fundamental cellular process regulated by zinc is the cell suicide process of apoptosis, also known as programmed cell death [6]. Zinc is abundant in brain and essential for brain development and function, so deficiency or excess of zinc has been shown to contribute to abnormal central nervous system development, alterations in behavior, and neurological disease. Zinc plays a key role in hippocampus-dependent learning and memory and brain-derived neurotrophic factor expression (BDNF) [7]. Synaptic Zn2? regulates synaptic plasticity and long-term potentiation (LTP), in turn contributing to learning and memory processes. There are three distinct pools of Zn in the brain: (1) a protein–metal complex pool; (2) an ionic or chelatable pool in the cytoplasm; and (3) a vesicular pool. About 10 % of total brain zinc is sequestered in synaptic vesicles in its free ionic form forming a subpopulation of ‘‘zinc enriched’’ neurons, which co-release zinc with the neurotransmitter glutamate from presynaptic glutamatergic nerve terminals into the synaptic cleft upon neuronal activation. The reaction between Zn and glutamatergic neurotransmission allows the ion to modulate the overall excitability of the brain and influence synaptic plasticity. Zn can act to either enhance or depress synaptic activity with different degrees of potency [8], so in principle, it can make the neurons more excitable [9], less excitable [10] or have no net effect [5].
The pathophysiology of Alzheimer’s disease At the beginning of the twenty-first century, AD is the most common form of adult-onset dementia, the fourth highest cause of disability and death in the elderly. It mainly occurs in elderly people and memory loss is commonly the presenting complaint. Initially, the patient has primarily shortterm memory loss which is called mild cognitive impairment (MCI). The symptoms of AD progress from mild memory loss to profound dementia and leads to intellectual decline. Clinically, AD represents a chronic progressive neurodegenerative disorder characterized by three primary groups of symptoms: (1) cognitive dysfunction including memory loss, language difficulties, and executive dysfunction, (2) non-cognitive symptoms: psychiatric and behavioral disturbances, and (3) difficulties with performing activities of daily living [11]. AD is characterized by abnormal deposition of protein aggregates in the form of extracellular plaques composed
123
of fibrillar Ab, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau, oxidative damage and neuronal death in the brain [12, 13]. Microscopically, the AD brain demonstrates shrinkage of large cortical neurons, selective neuronal damage and synapse loss in cortical areas of the brain essential for memory and higher mental functions [14]. According to the amyloid cascade hypothesis, the Ab aggregation and formation of amyloid plaques are the causative agents of Alzheimer’s pathology and the NFT, cell loss, and dementia follow as a direct result of this deposition [15]. The exact cause of AD is not clear, but a large body of studies has linked several risk factors with the disease [11]. Age is considered to be the main risk factor for AD. The second most important risk factor for AD is a positive family history, and individuals with a first-degree relative with AD show a three to fourfold age-corrected increase in risk. Other possible risk factors for AD include gender, lack of education, low linguistic ability in early life, head trauma and depression. Apolipoprotein E (ApoE) is a susceptibility factor for AD, and is considered as the strongest intrinsic risk for sporadic AD pathogenesis.
Zinc dyshomeostasis in Alzheimer’s disease Up to now the cause of progression and pathology of AD is far from fully elucidated. There has been mounting evidence implicating that an imbalance of metal homeostasis in the brain may play an important role in the pathogenesis of AD and related neurodegenerative diseases. Brain homeostasis of transition metals is severely perturbed in AD, with extracellular pooling of Zn and Cu in amyloid, and intraneuronal accumulation of Fe [16]. Zinc, second to iron, is one of the most abundant nutritionally essential elements in the human body. Bush et al. [17] provided the first biochemical evidence that Zn promotes the aggregation of Ab and the data suggest a role for cerebral Zn metabolism in the neuropathogenesis of AD and several other observations indicate that Zn metabolism is altered in AD (Table 1). A growing number of reports point to an abnormality in the uptake or distribution of Zn in AD brain [18, 19]. The regions of the brain with Ab plaques deposition are densely populated with zinc-enriched (ZEN) terminals, whereas regions with few Ab plaques have fewer ZEN terminals [20]. Previous studies have suggested that an extracellular elevation of the zinc concentration can initiate the deposition of Ab and lead to the formation of senile plaques. So there is a clear association between excess of zinc and the formation of amyloid plaques in AD. Therefore, the ability to regulate metal homeostasis offers the potential for the development of new therapies for the treatment of AD.
Neurol Sci Table 1 Zinc dyshomeostasis in Alzheimer’s disease References
Mechanism
Major conclusions
Yang et al. [7]
Decreased availability of synaptic zinc and BDNF deficit
High-dose supplementation of zinc impairs learning and memory
Bush et al. [17]
Zinc destabilization of human Ab 1–40 solution
Zn induces amyloid formation. First report that amyloid-b specifically and saturably binds and is precipitated by zinc
Stoltenberg et al. [21]
Increase of influx of zinc from plasma or loss of activity of neprilysin
Low dietary zinc results in a increase in plaque volume in the APP/PS1 mice
Religa et al. [22]
Zn accumulation causing the neuronal dysfunction that leads to dementia
Brain zinc accumulation is a prominent feature of advanced AD and is biochemically linked to brain amyloid-peptide accumulation and dementia severity in AD
Bush et al. [23]
Increase APP adhesiveness and interfere with APP catabolism
Excessive zinc concentrations may serve to accelerate Ab deposition in AD
Bush et al. [24]
Modifying APP adhesiveness to extracellular matrix elements
Extracellular zinc modulates the physiologic function of APP
Liu et al. [25]
Coordination of Zn2? to histidine-13
Zinc ion induces aggregation of Ab
An increasing body of evidence indicates that Zn2? is potentially damaging to neurons [14], and implicates Zn2? as a neurotoxin in models of stroke, epilepsy and AD. Exact mechanisms of Zn-mediated cell death are unclear, but numerous hypothetical mechanisms have been proposed [26, 27]. The dominant theory of Zn neurotoxicity is the hypothesis of transsynaptic movement of Zn2? (‘‘Zn2? translocation’’). This theory emphasizes the role of Zn which is released from presynaptic vesicles on activation, crosses the postsynaptic membrane, interacts with various types of channels and/or receptors on postsynaptic neurons to transmit or modulate neuronal signals (translocation) and finally causes neuronal death. Several studies indicate that Zn2? may act as a neurotransmitter and mediate apoptosis [26]. Biochemical studies have shown Zn to be actively involved in the amyloid dysmetabolism associated with AD [18]. Zn can activate kinases which can cause phosphorylation of the microtubule-associated protein tau. Phosphorylated tau is the main component of NFT, and, therefore, Zn may play a key role in changes of tau and subsequent NFT formation [28]. Zn2? can be taken up into mitochondria, from which it can be subsequently released in a Ca2?-dependent fashion [29]. Zn2? accumulation in mitochondria may not be benign, as Zn2? has been found to interfere with the function of isolated mitochondria and mitochondria are, therefore, likely to be the sites at which this cation induces injurious effects on neurons [30].
Zinc and oxidative stress in Alzheimer’s disease Oxidative stress in Alzheimer’s disease The exact etiology of AD progression is still unclear; however, increasing evidence indicates oxidative stress as
an early and sustained event in AD disease progression. Aberrant metal homeostasis may enhance the formation of ROS and Ab oligomerization and may, therefore, be a contributing factor in AD. AD brain exhibits marked oxidative damage of proteins, lipids and nucleic acids [31–33]. The oxidative damage is highly concentrated in and around amyloid plaques, but even extends to the neuropil which is devoid of Ab deposits [34]. Biometals, namely Cu, Zn and Fe, facilitate the oligomerisation of Ab, and imbalanced metal levels may contribute to the degenerative nature of AD through the uncontrolled generation of ROS. Markers of oxidative stress elevated in AD brain include lipid peroxidation, DNA oxidation, protein oxidation and reactive nitrogen species. Synthetic Ab peptides have been shown to induce lipid peroxidation of synaptosomes [35] and to be cytotoxic through mechanisms involving the generation of cellular superoxide radical (O2.) and H2O2 [36, 37], which can be abolished by superoxide dismutase (SOD) [38] and O2/ H2O2 scavengers [39]. H2O2 can readily cross biological membranes and H2O2-induced oxidative damage is associated with neurodegeneration. Emerging evidence suggests that production of H2O2 is central to Ab-induced cytotoxicity. It is established that mitochondrial dysfunction results in neurodegeneration and contributes to the pathogenesis of AD, potentially due to an increase in ROS [40]. Clioquinol plays an important role in the chelation and redistribution of metals in diseases characterized by Zn, Cu, Fe dyshomeostasis, such as AD, as it can reduce oxidation and Ab burden and attenuate the clinical symptoms of AD patients [41]. Another factor leading to oxidative stress is a reduced ability to cope with a rise in pro-oxidants such as Ab and there is evidence that major antioxidant defense systems are disturbed in AD [42]. Further evidence by Mao and
123
Neurol Sci
colleagues indicates that boosting intrinsic mitochondrial antioxidant defense system can offer some level of protection against AD-related insults and make the AbPP mice live longer, supporting that oxidative stress plays a primary role in AD etiopathology [43]. Thiol-reduced GSH normally accounts for the majority ([98 %) of total glutathione within the cell but it can also present as oxidized glutathione disulfide (GSSG). Several groups have independently confirmed reduced GSH levels and GSH/GSSG ratios in AD and MCI patients [44, 45]. Zinc may serve twin roles by both initiating amyloid deposition and then being involved in mechanisms attempting to quench oxidative stress and neurotoxicity derived from the amyloid mass.
Inhibition of stress response Zinc ions are redox-inert in biology, but they have important effects on redox metabolism. The capacity of Zn to protect the cell against oxidative damages, particularly to protect cellular sulfhydryl groups against oxidation and to inhibit the production of ROS by transition metals, has been elucidated and has led to the notion that zinc is an antioxidant [46]. Protection of thiol groups is thought to involve reduction of thiol reactivity through one of three possible mechanisms [47]: (1) direct binding of Zn to the thiol; (2) deactivation of the thiol by steric hindrance through binding to some other protein site close to the thiol group; (3) a conformational change elicited by Zn. Zn has properties advantageous for a role in cytoprotection as it can protect proteins and nucleic acids from oxidation and degradation, while stabilizing the microtubular cytoskeleton and cellular membranes [4, 48]. The conformational changes of Ab caused by Zn may be protective by preventing oxidizing metals (Fe3? and Cu2?) from interacting with Ab and the generation of H2O2 which can further damage the cell [49]. It is known that zinc prevents apoptotic cell death of nonneuronal cells, through inhibition of caspases suggesting a regulatory role for Zn2? in modulating the upstream apoptotic mechanism [50]. Influx of Zn into neurons may be a homeostatic response to apoptotic signals. Zn is capable of decreasing postischemic injury in a variety of tissues and organs through the mechanism that might involve the inhibition of copper reactivity. Zn shares some features with Bcl-2, an anti-apoptotic protein, which also has anti-oxidant properties [51].
Promotion of stress response Although zinc is not an oxidant itself, several lines of evidence indicate that zinc toxicity is largely due to
123
oxidative stress. First, zinc-induced necrotic neuronal degeneration is accompanied by increased levels of toxic free radicals [52]. Second, zinc-induced cell death is prevented by various antioxidants (vitamin E analog trolox) [53]. Last, superoxide-producing enzymes, such as NADPH oxidase, are induced and activated after zinc exposure, and their inhibitors attenuate cortical neuronal death induced by zinc [54]. Zn has been known to be an inhibitor of many enzymes, when inhibiting some important metabolic enzymes, Zn interferes with generation of energy. Mitochondrial respiration is particularly sensitive to Zn and mitochondrial fluctuations of Zn change the amount of ROS produced by respiration [55]. Outside of its physiological range, zinc is a pro-oxidant and elicits oxidative stress. Both Zn overload and Zn deficiency induce oxidative stress that can cause the death of nerve cells [2, 56]. Depletion of Zn in culture media is followed by DNA fragmentation, activation of caspase-3, and morphologic changes. Chronic zinc deprivation can lead to increased sensitivity to some oxidative stress [46]. If the capacity of the homeostatic system to handle zinc is exhausted, Zn overload elicits oxidative stress by inhibiting cellular energy and increasing generation of ROS [57]. Oxidative stress is a corollary of both Zn deficiency and Zn overload and affects cellular Zn distribution. It is noted that tight control of zinc is necessary to avoid oxidative stress.
Zinc: a potential therapeutic target in Alzheimer’s disease Metal chelation is a potential therapeutic strategy for AD, because zinc is involved in the deposition and stabilization of amyloid plaques, and chelating agents can dissolve amyloid deposits in vitro and in vivo. Up to now, the most important class of drugs developed for counteracting Zn2? deregulation is the so-called metal-protein attenuation compounds (MPACs) [58]. MPACs can remove Zn2? from Ab and relocate the cation to sites where it can be beneficial. Among the MPACs, Clioquinol (CQ), an 8-OH quinoline with moderate affinity for Zn, inhibits metalinduced Ab aggregation and ROS generation in vitro [59]. The study by Cherny reported 49 % decrease in brain Ab deposition in APP2576 transgenic mice treated orally for 9 weeks with CQ compared to untreated mice [60]. CQ can cross the blood–brain barrier (BBB) and was able to increase brain zinc levels in treated mice. In a Phase 2 clinical trial, treatment of CQ in moderately severe AD patients for 36 weeks slowed the rate of cognitive decline, caused reduction in plasma Ab42 levels and rise in plasma zinc levels as compared to placebo controls [61]. Recent studies indicate that CQ (and probably CQ-related compounds) might also favor the buffering of synaptic Zn and
Neurol Sci
inhibit the deposition of toxic Ab oligomers in the synaptic cleft [59, 62]. PBT-2, the second generation 8-OH quinoline derivative of CQ, has shown the most promising results by serving as metal exchanger and ionophore. In AD patients, PBT2 reduces CSF Ab levels and promotes cognitive improvement [63, 64].
Conclusion Like calcium, zinc plays essential roles in a myriad of essential neurological processes. Disturbances in the metabolism of Zn from environmental or genetic factors are central to both the aggregation of Ab and oxidative damage associated with AD. The evidence cited by this review indicates that abnormal interactions with Zn are upstream in the AD pathophysiology, and represent an attractive novel drug target. ‘The Metal Hypothesis of Alzheimer’s Disease’ has become the basis of several drug discovery programs, such as CQ and PTB2. Although zinc dyshomeostasis may contribute to the development of AD from numerous studies, further more detailed work is required to clarify the molecular and cellular mechanisms affected by zinc under both normal and disease situations and to elucidate the existing contradictory results.
References 1. Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240 2. Hao Q, Maret W (2005) Imbalance between pro-oxidant and proantioxidant functions of zinc in disease. J Alzheimers Dis 8:161–170 discussion 209-115 3. Hensley K, Hall N, Subramaniam R, Cole P, Harris M et al (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156 4. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118 5. Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462 6. Wyllie AH (1997) Apoptosis: an overview. Br Med Bull 53:451–465 7. Yang Y, Jing XP, Zhang SP, Gu RX, Tang FX et al (2013) High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling. PLoS One 8:e55384 8. Paoletti P, Vergnano AM, Barbour B, Casado M (2009) Zinc at glutamatergic synapses. Neuroscience 158:126–136 9. Mayer ML, Vyklicky L Jr (1989) The action of zinc on synaptic transmission and neuronal excitability in cultures of mouse hippocampus. J Physiol 415:351–365 10. Draguhn A, Verdorn TA, Ewert M, Seeburg PH, Sakmann B (1990) Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2?. Neuron 5:781– 788 11. Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158
12. Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781 13. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112 14. Lyubartseva G, Lovell MA (2012) A potential role for zinc alterations in the pathogenesis of Alzheimer’s disease. Biofactors 38:98–106 15. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185 16. Bush AI (2013) The metal theory of Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S277–S281 17. Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP et al (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464–1467 18. Cuajungco MP, Lees GJ (1997) Zinc and Alzheimer’s disease: is there a direct link? Brain Res Brain Res Rev 23:219–236 19. Cuajungco MP, Lees GJ (1997) Zinc metabolism in the brain: relevance to human neurodegenerative disorders. Neurobiol Dis 4:137–169 20. Zhang LH, Wang X, Stoltenberg M, Danscher G, Huang L et al (2008) Abundant expression of zinc transporters in the amyloid plaques of Alzheimer’s disease brain. Brain Res Bull 77:55–60 21. Stoltenberg M, Bush AI, Bach G, Smidt K, Larsen A et al (2007) Amyloid plaques arise from zinc-enriched cortical layers in APP/ PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency. Neuroscience 150:357–369 22. Religa D, Strozyk D, Cherny RA, Volitakis I, Haroutunian V et al (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69–75 23. Bush AI, Pettingell WH Jr, Paradis MD, Tanzi RE (1994) Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem 269:12152–12158 24. Bush AI, Pettingell WH Jr, de Paradis M, Tanzi RE, Wasco W (1994) The amyloid beta-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily. J Biol Chem 269:26618–26621 25. Liu ST, Howlett G, Barrow CJ (1999) Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer’s disease. Biochemistry 38:9373–9378 26. Capasso M, Jeng JM, Malavolta M, Mocchegiani E, Sensi SL (2005) Zinc dyshomeostasis: a key modulator of neuronal injury. J Alzheimers Dis 8:93–108 discussion 209-115 27. Zatta P, Lucchini R, van Rensburg SJ, Taylor A (2003) The role of metals in neurodegenerative processes: aluminum, manganese, and zinc. Brain Res Bull 62:15–28 28. An WL, Bjorkdahl C, Liu R, Cowburn RF, Winblad B et al (2005) Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3b in SH-SY5Y neuroblastoma cells. J Neurochem 92:1104–1115 29. Sensi SL, Ton-That D, Weiss JH (2002) Mitochondrial sequestration and Ca(2?)-dependent release of cytosolic Zn(2?) loads in cortical neurons. Neurobiol Dis 10:100–108 30. Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH (1999) Preferential Zn2? influx through Ca2?-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc Natl Acad Sci USA 96:2414–2419 31. Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187 32. Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF et al (1998) Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine. J Histochem Cytochem 46:731–735
123
Neurol Sci 33. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL et al (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215 34. Maynard CJ, Cappai R, Volitakis I, Laughton KM, Masters CL et al (2009) Chronic exposure to high levels of zinc or copper has little effect on brain metal homeostasis or Abeta accumulation in transgenic APP-C100 mice. Cell Mol Neurobiol 29:757–767 35. Butterfield DA, Hensley K, Harris M, Mattson M, Carney J (1994) Beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem Biophys Res Commun 200:710–715 36. Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817–827 37. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M et al (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91:3270–3274 38. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171 39. Bruce AJ, Malfroy B, Baudry M (1996) beta-Amyloid toxicity in organotypic hippocampal cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. Proc Natl Acad Sci USA 93:2312–2316 40. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505 41. Bareggi SR, Cornelli U (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 18:41–46 42. Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int 62:540–555 43. Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP et al (2012) Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer’s disease: implications for neuroprotection and lifespan extension. Hum Mol Genet 21:2973–2990 44. Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM et al (2011) Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 26:59–68 45. Vina J, Lloret A, Orti R, Alonso D (2004) Molecular bases of the treatment of Alzheimer’s disease with antioxidants: prevention of oxidative stress. Mol Asp Med 25:117–123 46. Powell SR (2000) The antioxidant properties of zinc. J Nutr 130:1447S–1454S 47. Gibbs PN, Gore MG, Jordan PM (1985) Investigation of the effect of metal ions on the reactivity of thiol groups in human 5-aminolaevulinate dehydratase. Biochem J 225:573–580 48. Da Silva JJR (1991) Zinc: Lewis acid catalysis and regulation. In: Williams RJ (ed) The Biological Chemistry of the Elements. Clarendon Press, Oxford, pp 299–318 49. Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT et al (2000) Evidence that the beta-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 275:19439–19442
123
50. Perry DK, Smyth MJ, Stennicke HR, Salvesen GS, Duriez P et al (1997) Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis. J Biol Chem 272:18530–18533 51. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 4:327–332 52. Sensi SL, Yin HZ, Weiss JH (1999) Glutamate triggers preferential Zn2? flux through Ca2? permeable AMPA channels and consequent ROS production. Neuroreport 10:1723–1727 53. Seo SR, Chong SA, Lee SI, Sung JY, Ahn YS et al (2001) Zn2? -induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells. J Neurochem 78:600–610 54. Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111 55. Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR et al (2003) Modulation of mitochondrial function by endogenous Zn2? pools. Proc Natl Acad Sci USA 100:6157–6162 56. Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD (2001) The role of zinc in caspase activation and apoptotic cell death. Biometals 14:315–330 57. Dineley KE, Votyakova TV, Reynolds IJ (2003) Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem 85:563–570 58. Corona C, Pensalfini A, Frazzini V, Sensi SL (2011) New therapeutic targets in Alzheimer’s disease: brain deregulation of calcium and zinc. Cell Death Dis 2:e176 59. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E et al (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59:43–55 60. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD et al (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676 61. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691 62. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004–4015 63. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7:779–786 64. Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A et al (2010) PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 20:509–516
REVIEW ARTICLE
Zinc and its effects on oxidative stress in Alzheimer’s disease Ye Yuan • Fenglan Niu • Ya Liu • Na Lu
Received: 22 October 2013 / Accepted: 29 January 2014 Ó Springer-Verlag Italia 2014
Abstract Alzheimer’s disease (AD) is a progressive agerelated neurodegenerative disorder. The patho-physiological characteristic of AD is abnormal deposition of fibrillar amyloid b protein, intracellular neurofibrillary tangles, oxidative damage and neuronal death in the brain. Zinc is an important trace element in human body regulating many physiological processes. Increasing evidence suggests that the etiology of AD may involve disruptions of zinc homeostasis, and oxidative stress facilitating reactive oxygen species production is an early and sustained event in AD disease progression. Both Zn deficiency and Zn overload may affect cellular Zn distribution and be linked to neurodegeneration in AD. Meanwhile, Zn may play paradoxical roles in initiating and inhibiting oxidative stress and neurotoxicity. This review will focus on aspects of the role of zinc in AD, which includes a large body of research regarding zinc dyshomeostasis and its relation with oxidative stress. Keywords Alzheimer’s disease Zinc Oxidative stress Neurodegeneration
Y. Yuan The Department of Anesthesiology, The First Bethune Hospital of Jilin University, Changchun, People’s Republic of China F. Niu Y. Liu The School of Public Health, Jilin University, Changchun, People’s Republic of China N. Lu (&) The Department of Pediatrics, The First Bethune Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun 130021, People’s Republic of China e-mail: [email protected]
Introduction Alzheimer’s disease (AD) is the most common dementia and accounts for an estimated 60–80 % of cases in Western societies. But the cause of progression and pathology of AD is not very clear. Different concepts of the etiology of AD exist including the ‘metal hypothesis’ which has attracted increasing attention in recent two decades [1]. The hypothesis focuses on the disease-associated alterations of metals in the brain which participate in the cascade of pathogenic events that finally cause the clinical symptoms. Metal ions play a key role in synaptic function and their homeostasis is tightly regulated. Among the important essential trace metals, zinc has a variety of functions in hundreds of enzymes and protein domains with different types of zinc finger motifs [2]. Our understanding of the roles played by zinc in the physiological and pathological functioning of the brain is rapidly increasing. Brain zinc accumulation is a prominent feature of advanced AD and is biochemically linked to brain amyloid b-peptide (Ab) accumulation and dementia severity in AD. So a breakdown in this metal homeostasis and the generation of toxic Ab oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Meanwhile, abnormal metal homeostasis may enhance the production of reactive oxygen species (ROS) and finally contribute to AD. A relationship exists between signs of oxidative stress and Ab accumulation in AD brain [3]. In this review, we summarize the knowledge of the physiological role of zinc, zinc dyshomeostasis, and its effects on oxidative stress in AD.
Physiological role of zinc in the brain Zinc is one of the most important trace elements in human body which is essential for many physiological processes
123
Neurol Sci
such as cell proliferation and differentiation, growth and development, and enzymatic activity regulation. Zn is also involved in hormonal storage and release, neurotransmission and memory [4], acting similar to calcium as a second messenger, so zinc is also called ‘‘the calcium of the twenty-first century’’ [5]. Another fundamental cellular process regulated by zinc is the cell suicide process of apoptosis, also known as programmed cell death [6]. Zinc is abundant in brain and essential for brain development and function, so deficiency or excess of zinc has been shown to contribute to abnormal central nervous system development, alterations in behavior, and neurological disease. Zinc plays a key role in hippocampus-dependent learning and memory and brain-derived neurotrophic factor expression (BDNF) [7]. Synaptic Zn2? regulates synaptic plasticity and long-term potentiation (LTP), in turn contributing to learning and memory processes. There are three distinct pools of Zn in the brain: (1) a protein–metal complex pool; (2) an ionic or chelatable pool in the cytoplasm; and (3) a vesicular pool. About 10 % of total brain zinc is sequestered in synaptic vesicles in its free ionic form forming a subpopulation of ‘‘zinc enriched’’ neurons, which co-release zinc with the neurotransmitter glutamate from presynaptic glutamatergic nerve terminals into the synaptic cleft upon neuronal activation. The reaction between Zn and glutamatergic neurotransmission allows the ion to modulate the overall excitability of the brain and influence synaptic plasticity. Zn can act to either enhance or depress synaptic activity with different degrees of potency [8], so in principle, it can make the neurons more excitable [9], less excitable [10] or have no net effect [5].
The pathophysiology of Alzheimer’s disease At the beginning of the twenty-first century, AD is the most common form of adult-onset dementia, the fourth highest cause of disability and death in the elderly. It mainly occurs in elderly people and memory loss is commonly the presenting complaint. Initially, the patient has primarily shortterm memory loss which is called mild cognitive impairment (MCI). The symptoms of AD progress from mild memory loss to profound dementia and leads to intellectual decline. Clinically, AD represents a chronic progressive neurodegenerative disorder characterized by three primary groups of symptoms: (1) cognitive dysfunction including memory loss, language difficulties, and executive dysfunction, (2) non-cognitive symptoms: psychiatric and behavioral disturbances, and (3) difficulties with performing activities of daily living [11]. AD is characterized by abnormal deposition of protein aggregates in the form of extracellular plaques composed
123
of fibrillar Ab, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau, oxidative damage and neuronal death in the brain [12, 13]. Microscopically, the AD brain demonstrates shrinkage of large cortical neurons, selective neuronal damage and synapse loss in cortical areas of the brain essential for memory and higher mental functions [14]. According to the amyloid cascade hypothesis, the Ab aggregation and formation of amyloid plaques are the causative agents of Alzheimer’s pathology and the NFT, cell loss, and dementia follow as a direct result of this deposition [15]. The exact cause of AD is not clear, but a large body of studies has linked several risk factors with the disease [11]. Age is considered to be the main risk factor for AD. The second most important risk factor for AD is a positive family history, and individuals with a first-degree relative with AD show a three to fourfold age-corrected increase in risk. Other possible risk factors for AD include gender, lack of education, low linguistic ability in early life, head trauma and depression. Apolipoprotein E (ApoE) is a susceptibility factor for AD, and is considered as the strongest intrinsic risk for sporadic AD pathogenesis.
Zinc dyshomeostasis in Alzheimer’s disease Up to now the cause of progression and pathology of AD is far from fully elucidated. There has been mounting evidence implicating that an imbalance of metal homeostasis in the brain may play an important role in the pathogenesis of AD and related neurodegenerative diseases. Brain homeostasis of transition metals is severely perturbed in AD, with extracellular pooling of Zn and Cu in amyloid, and intraneuronal accumulation of Fe [16]. Zinc, second to iron, is one of the most abundant nutritionally essential elements in the human body. Bush et al. [17] provided the first biochemical evidence that Zn promotes the aggregation of Ab and the data suggest a role for cerebral Zn metabolism in the neuropathogenesis of AD and several other observations indicate that Zn metabolism is altered in AD (Table 1). A growing number of reports point to an abnormality in the uptake or distribution of Zn in AD brain [18, 19]. The regions of the brain with Ab plaques deposition are densely populated with zinc-enriched (ZEN) terminals, whereas regions with few Ab plaques have fewer ZEN terminals [20]. Previous studies have suggested that an extracellular elevation of the zinc concentration can initiate the deposition of Ab and lead to the formation of senile plaques. So there is a clear association between excess of zinc and the formation of amyloid plaques in AD. Therefore, the ability to regulate metal homeostasis offers the potential for the development of new therapies for the treatment of AD.
Neurol Sci Table 1 Zinc dyshomeostasis in Alzheimer’s disease References
Mechanism
Major conclusions
Yang et al. [7]
Decreased availability of synaptic zinc and BDNF deficit
High-dose supplementation of zinc impairs learning and memory
Bush et al. [17]
Zinc destabilization of human Ab 1–40 solution
Zn induces amyloid formation. First report that amyloid-b specifically and saturably binds and is precipitated by zinc
Stoltenberg et al. [21]
Increase of influx of zinc from plasma or loss of activity of neprilysin
Low dietary zinc results in a increase in plaque volume in the APP/PS1 mice
Religa et al. [22]
Zn accumulation causing the neuronal dysfunction that leads to dementia
Brain zinc accumulation is a prominent feature of advanced AD and is biochemically linked to brain amyloid-peptide accumulation and dementia severity in AD
Bush et al. [23]
Increase APP adhesiveness and interfere with APP catabolism
Excessive zinc concentrations may serve to accelerate Ab deposition in AD
Bush et al. [24]
Modifying APP adhesiveness to extracellular matrix elements
Extracellular zinc modulates the physiologic function of APP
Liu et al. [25]
Coordination of Zn2? to histidine-13
Zinc ion induces aggregation of Ab
An increasing body of evidence indicates that Zn2? is potentially damaging to neurons [14], and implicates Zn2? as a neurotoxin in models of stroke, epilepsy and AD. Exact mechanisms of Zn-mediated cell death are unclear, but numerous hypothetical mechanisms have been proposed [26, 27]. The dominant theory of Zn neurotoxicity is the hypothesis of transsynaptic movement of Zn2? (‘‘Zn2? translocation’’). This theory emphasizes the role of Zn which is released from presynaptic vesicles on activation, crosses the postsynaptic membrane, interacts with various types of channels and/or receptors on postsynaptic neurons to transmit or modulate neuronal signals (translocation) and finally causes neuronal death. Several studies indicate that Zn2? may act as a neurotransmitter and mediate apoptosis [26]. Biochemical studies have shown Zn to be actively involved in the amyloid dysmetabolism associated with AD [18]. Zn can activate kinases which can cause phosphorylation of the microtubule-associated protein tau. Phosphorylated tau is the main component of NFT, and, therefore, Zn may play a key role in changes of tau and subsequent NFT formation [28]. Zn2? can be taken up into mitochondria, from which it can be subsequently released in a Ca2?-dependent fashion [29]. Zn2? accumulation in mitochondria may not be benign, as Zn2? has been found to interfere with the function of isolated mitochondria and mitochondria are, therefore, likely to be the sites at which this cation induces injurious effects on neurons [30].
Zinc and oxidative stress in Alzheimer’s disease Oxidative stress in Alzheimer’s disease The exact etiology of AD progression is still unclear; however, increasing evidence indicates oxidative stress as
an early and sustained event in AD disease progression. Aberrant metal homeostasis may enhance the formation of ROS and Ab oligomerization and may, therefore, be a contributing factor in AD. AD brain exhibits marked oxidative damage of proteins, lipids and nucleic acids [31–33]. The oxidative damage is highly concentrated in and around amyloid plaques, but even extends to the neuropil which is devoid of Ab deposits [34]. Biometals, namely Cu, Zn and Fe, facilitate the oligomerisation of Ab, and imbalanced metal levels may contribute to the degenerative nature of AD through the uncontrolled generation of ROS. Markers of oxidative stress elevated in AD brain include lipid peroxidation, DNA oxidation, protein oxidation and reactive nitrogen species. Synthetic Ab peptides have been shown to induce lipid peroxidation of synaptosomes [35] and to be cytotoxic through mechanisms involving the generation of cellular superoxide radical (O2.) and H2O2 [36, 37], which can be abolished by superoxide dismutase (SOD) [38] and O2/ H2O2 scavengers [39]. H2O2 can readily cross biological membranes and H2O2-induced oxidative damage is associated with neurodegeneration. Emerging evidence suggests that production of H2O2 is central to Ab-induced cytotoxicity. It is established that mitochondrial dysfunction results in neurodegeneration and contributes to the pathogenesis of AD, potentially due to an increase in ROS [40]. Clioquinol plays an important role in the chelation and redistribution of metals in diseases characterized by Zn, Cu, Fe dyshomeostasis, such as AD, as it can reduce oxidation and Ab burden and attenuate the clinical symptoms of AD patients [41]. Another factor leading to oxidative stress is a reduced ability to cope with a rise in pro-oxidants such as Ab and there is evidence that major antioxidant defense systems are disturbed in AD [42]. Further evidence by Mao and
123
Neurol Sci
colleagues indicates that boosting intrinsic mitochondrial antioxidant defense system can offer some level of protection against AD-related insults and make the AbPP mice live longer, supporting that oxidative stress plays a primary role in AD etiopathology [43]. Thiol-reduced GSH normally accounts for the majority ([98 %) of total glutathione within the cell but it can also present as oxidized glutathione disulfide (GSSG). Several groups have independently confirmed reduced GSH levels and GSH/GSSG ratios in AD and MCI patients [44, 45]. Zinc may serve twin roles by both initiating amyloid deposition and then being involved in mechanisms attempting to quench oxidative stress and neurotoxicity derived from the amyloid mass.
Inhibition of stress response Zinc ions are redox-inert in biology, but they have important effects on redox metabolism. The capacity of Zn to protect the cell against oxidative damages, particularly to protect cellular sulfhydryl groups against oxidation and to inhibit the production of ROS by transition metals, has been elucidated and has led to the notion that zinc is an antioxidant [46]. Protection of thiol groups is thought to involve reduction of thiol reactivity through one of three possible mechanisms [47]: (1) direct binding of Zn to the thiol; (2) deactivation of the thiol by steric hindrance through binding to some other protein site close to the thiol group; (3) a conformational change elicited by Zn. Zn has properties advantageous for a role in cytoprotection as it can protect proteins and nucleic acids from oxidation and degradation, while stabilizing the microtubular cytoskeleton and cellular membranes [4, 48]. The conformational changes of Ab caused by Zn may be protective by preventing oxidizing metals (Fe3? and Cu2?) from interacting with Ab and the generation of H2O2 which can further damage the cell [49]. It is known that zinc prevents apoptotic cell death of nonneuronal cells, through inhibition of caspases suggesting a regulatory role for Zn2? in modulating the upstream apoptotic mechanism [50]. Influx of Zn into neurons may be a homeostatic response to apoptotic signals. Zn is capable of decreasing postischemic injury in a variety of tissues and organs through the mechanism that might involve the inhibition of copper reactivity. Zn shares some features with Bcl-2, an anti-apoptotic protein, which also has anti-oxidant properties [51].
Promotion of stress response Although zinc is not an oxidant itself, several lines of evidence indicate that zinc toxicity is largely due to
123
oxidative stress. First, zinc-induced necrotic neuronal degeneration is accompanied by increased levels of toxic free radicals [52]. Second, zinc-induced cell death is prevented by various antioxidants (vitamin E analog trolox) [53]. Last, superoxide-producing enzymes, such as NADPH oxidase, are induced and activated after zinc exposure, and their inhibitors attenuate cortical neuronal death induced by zinc [54]. Zn has been known to be an inhibitor of many enzymes, when inhibiting some important metabolic enzymes, Zn interferes with generation of energy. Mitochondrial respiration is particularly sensitive to Zn and mitochondrial fluctuations of Zn change the amount of ROS produced by respiration [55]. Outside of its physiological range, zinc is a pro-oxidant and elicits oxidative stress. Both Zn overload and Zn deficiency induce oxidative stress that can cause the death of nerve cells [2, 56]. Depletion of Zn in culture media is followed by DNA fragmentation, activation of caspase-3, and morphologic changes. Chronic zinc deprivation can lead to increased sensitivity to some oxidative stress [46]. If the capacity of the homeostatic system to handle zinc is exhausted, Zn overload elicits oxidative stress by inhibiting cellular energy and increasing generation of ROS [57]. Oxidative stress is a corollary of both Zn deficiency and Zn overload and affects cellular Zn distribution. It is noted that tight control of zinc is necessary to avoid oxidative stress.
Zinc: a potential therapeutic target in Alzheimer’s disease Metal chelation is a potential therapeutic strategy for AD, because zinc is involved in the deposition and stabilization of amyloid plaques, and chelating agents can dissolve amyloid deposits in vitro and in vivo. Up to now, the most important class of drugs developed for counteracting Zn2? deregulation is the so-called metal-protein attenuation compounds (MPACs) [58]. MPACs can remove Zn2? from Ab and relocate the cation to sites where it can be beneficial. Among the MPACs, Clioquinol (CQ), an 8-OH quinoline with moderate affinity for Zn, inhibits metalinduced Ab aggregation and ROS generation in vitro [59]. The study by Cherny reported 49 % decrease in brain Ab deposition in APP2576 transgenic mice treated orally for 9 weeks with CQ compared to untreated mice [60]. CQ can cross the blood–brain barrier (BBB) and was able to increase brain zinc levels in treated mice. In a Phase 2 clinical trial, treatment of CQ in moderately severe AD patients for 36 weeks slowed the rate of cognitive decline, caused reduction in plasma Ab42 levels and rise in plasma zinc levels as compared to placebo controls [61]. Recent studies indicate that CQ (and probably CQ-related compounds) might also favor the buffering of synaptic Zn and
Neurol Sci
inhibit the deposition of toxic Ab oligomers in the synaptic cleft [59, 62]. PBT-2, the second generation 8-OH quinoline derivative of CQ, has shown the most promising results by serving as metal exchanger and ionophore. In AD patients, PBT2 reduces CSF Ab levels and promotes cognitive improvement [63, 64].
Conclusion Like calcium, zinc plays essential roles in a myriad of essential neurological processes. Disturbances in the metabolism of Zn from environmental or genetic factors are central to both the aggregation of Ab and oxidative damage associated with AD. The evidence cited by this review indicates that abnormal interactions with Zn are upstream in the AD pathophysiology, and represent an attractive novel drug target. ‘The Metal Hypothesis of Alzheimer’s Disease’ has become the basis of several drug discovery programs, such as CQ and PTB2. Although zinc dyshomeostasis may contribute to the development of AD from numerous studies, further more detailed work is required to clarify the molecular and cellular mechanisms affected by zinc under both normal and disease situations and to elucidate the existing contradictory results.
References 1. Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240 2. Hao Q, Maret W (2005) Imbalance between pro-oxidant and proantioxidant functions of zinc in disease. J Alzheimers Dis 8:161–170 discussion 209-115 3. Hensley K, Hall N, Subramaniam R, Cole P, Harris M et al (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156 4. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118 5. Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462 6. Wyllie AH (1997) Apoptosis: an overview. Br Med Bull 53:451–465 7. Yang Y, Jing XP, Zhang SP, Gu RX, Tang FX et al (2013) High dose zinc supplementation induces hippocampal zinc deficiency and memory impairment with inhibition of BDNF signaling. PLoS One 8:e55384 8. Paoletti P, Vergnano AM, Barbour B, Casado M (2009) Zinc at glutamatergic synapses. Neuroscience 158:126–136 9. Mayer ML, Vyklicky L Jr (1989) The action of zinc on synaptic transmission and neuronal excitability in cultures of mouse hippocampus. J Physiol 415:351–365 10. Draguhn A, Verdorn TA, Ewert M, Seeburg PH, Sakmann B (1990) Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2?. Neuron 5:781– 788 11. Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158
12. Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781 13. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112 14. Lyubartseva G, Lovell MA (2012) A potential role for zinc alterations in the pathogenesis of Alzheimer’s disease. Biofactors 38:98–106 15. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185 16. Bush AI (2013) The metal theory of Alzheimer’s disease. J Alzheimers Dis 33(Suppl 1):S277–S281 17. Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP et al (1994) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464–1467 18. Cuajungco MP, Lees GJ (1997) Zinc and Alzheimer’s disease: is there a direct link? Brain Res Brain Res Rev 23:219–236 19. Cuajungco MP, Lees GJ (1997) Zinc metabolism in the brain: relevance to human neurodegenerative disorders. Neurobiol Dis 4:137–169 20. Zhang LH, Wang X, Stoltenberg M, Danscher G, Huang L et al (2008) Abundant expression of zinc transporters in the amyloid plaques of Alzheimer’s disease brain. Brain Res Bull 77:55–60 21. Stoltenberg M, Bush AI, Bach G, Smidt K, Larsen A et al (2007) Amyloid plaques arise from zinc-enriched cortical layers in APP/ PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency. Neuroscience 150:357–369 22. Religa D, Strozyk D, Cherny RA, Volitakis I, Haroutunian V et al (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69–75 23. Bush AI, Pettingell WH Jr, Paradis MD, Tanzi RE (1994) Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem 269:12152–12158 24. Bush AI, Pettingell WH Jr, de Paradis M, Tanzi RE, Wasco W (1994) The amyloid beta-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily. J Biol Chem 269:26618–26621 25. Liu ST, Howlett G, Barrow CJ (1999) Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer’s disease. Biochemistry 38:9373–9378 26. Capasso M, Jeng JM, Malavolta M, Mocchegiani E, Sensi SL (2005) Zinc dyshomeostasis: a key modulator of neuronal injury. J Alzheimers Dis 8:93–108 discussion 209-115 27. Zatta P, Lucchini R, van Rensburg SJ, Taylor A (2003) The role of metals in neurodegenerative processes: aluminum, manganese, and zinc. Brain Res Bull 62:15–28 28. An WL, Bjorkdahl C, Liu R, Cowburn RF, Winblad B et al (2005) Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3b in SH-SY5Y neuroblastoma cells. J Neurochem 92:1104–1115 29. Sensi SL, Ton-That D, Weiss JH (2002) Mitochondrial sequestration and Ca(2?)-dependent release of cytosolic Zn(2?) loads in cortical neurons. Neurobiol Dis 10:100–108 30. Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH (1999) Preferential Zn2? influx through Ca2?-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc Natl Acad Sci USA 96:2414–2419 31. Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187 32. Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF et al (1998) Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine. J Histochem Cytochem 46:731–735
123
Neurol Sci 33. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL et al (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70:2212–2215 34. Maynard CJ, Cappai R, Volitakis I, Laughton KM, Masters CL et al (2009) Chronic exposure to high levels of zinc or copper has little effect on brain metal homeostasis or Abeta accumulation in transgenic APP-C100 mice. Cell Mol Neurobiol 29:757–767 35. Butterfield DA, Hensley K, Harris M, Mattson M, Carney J (1994) Beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem Biophys Res Commun 200:710–715 36. Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77:817–827 37. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M et al (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91:3270–3274 38. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380:168–171 39. Bruce AJ, Malfroy B, Baudry M (1996) beta-Amyloid toxicity in organotypic hippocampal cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. Proc Natl Acad Sci USA 93:2312–2316 40. Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505 41. Bareggi SR, Cornelli U (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 18:41–46 42. Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int 62:540–555 43. Mao P, Manczak M, Calkins MJ, Truong Q, Reddy TP et al (2012) Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer’s disease: implications for neuroprotection and lifespan extension. Hum Mol Genet 21:2973–2990 44. Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM et al (2011) Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 26:59–68 45. Vina J, Lloret A, Orti R, Alonso D (2004) Molecular bases of the treatment of Alzheimer’s disease with antioxidants: prevention of oxidative stress. Mol Asp Med 25:117–123 46. Powell SR (2000) The antioxidant properties of zinc. J Nutr 130:1447S–1454S 47. Gibbs PN, Gore MG, Jordan PM (1985) Investigation of the effect of metal ions on the reactivity of thiol groups in human 5-aminolaevulinate dehydratase. Biochem J 225:573–580 48. Da Silva JJR (1991) Zinc: Lewis acid catalysis and regulation. In: Williams RJ (ed) The Biological Chemistry of the Elements. Clarendon Press, Oxford, pp 299–318 49. Cuajungco MP, Goldstein LE, Nunomura A, Smith MA, Lim JT et al (2000) Evidence that the beta-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of abeta by zinc. J Biol Chem 275:19439–19442
123
50. Perry DK, Smyth MJ, Stennicke HR, Salvesen GS, Duriez P et al (1997) Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis. J Biol Chem 272:18530–18533 51. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN (1993) Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 4:327–332 52. Sensi SL, Yin HZ, Weiss JH (1999) Glutamate triggers preferential Zn2? flux through Ca2? permeable AMPA channels and consequent ROS production. Neuroreport 10:1723–1727 53. Seo SR, Chong SA, Lee SI, Sung JY, Ahn YS et al (2001) Zn2? -induced ERK activation mediated by reactive oxygen species causes cell death in differentiated PC12 cells. J Neurochem 78:600–610 54. Noh KM, Koh JY (2000) Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J Neurosci 20:RC111 55. Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR et al (2003) Modulation of mitochondrial function by endogenous Zn2? pools. Proc Natl Acad Sci USA 100:6157–6162 56. Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD (2001) The role of zinc in caspase activation and apoptotic cell death. Biometals 14:315–330 57. Dineley KE, Votyakova TV, Reynolds IJ (2003) Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. J Neurochem 85:563–570 58. Corona C, Pensalfini A, Frazzini V, Sensi SL (2011) New therapeutic targets in Alzheimer’s disease: brain deregulation of calcium and zinc. Cell Death Dis 2:e176 59. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E et al (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59:43–55 60. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD et al (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676 61. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691 62. Deshpande A, Kawai H, Metherate R, Glabe CG, Busciglio J (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004–4015 63. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7:779–786 64. Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A et al (2010) PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 20:509–516
