Zinc, in Alzheimer’s disease

Lovell M A, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. 1998. Copper, iron and zinc in Alzheimer s disease senile plaques. J Neurol Sci 158 47-52. 

Lovell MA, Robertson ID, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer s disease senile plaques. J Neurol Sci 158 47-52 Lu Z, Nie G, Li Y, Soe-Lin S, Tao Y, Cao Y, Zhang Z, Liu N, Ponka P, Zhao B (2009) Overexpression of Mitochondrial Ferritin Sensitizes Cells to Oxidative Stress Via an Iron-Mediated Mechanism. Antioxid Redox Signal 11(8) 1791-1803 Luchsinger JA, Tang MX, Shea S, Mayeux R (2003) Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 60 203-208... 

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, GaskeU PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer s disease in late onset families. Science 261 921-923 Cornett CR, Markesbery WR, Ehmann WD (1998) Imbalances of trace elements related to oxidative damage in Alzheimer s disease brain. Neurotoxicology 19 339-345 Corrigan FM, Reynolds GP, Ward NI (1993) Hippocampal tin, aluminum and zinc in Alzheimer s disease. Biometals 6 149-154... 

Calcineurin is a serine/threonine protein phosphatase widely distributed in the brain, but its role in brain function remains unknown. It is critical for several important cellular processes including T-cell activation, and recent data indicate that it may be involved in hyperphosphorylation of tau in Alzheimer s disease (600, 601). The active site of native calcineurin contains zinc and iron metal ions and three metal-bound water molecules (602), one of which may be involved in nucleophilic attack on the substrate. Compound 119 (FK506, tacroli-... 

Figure 18.16 Hypothetical model for the metallobiology of AP in Alzheimer s disease. (From Bush, 2003. Copyright 2003, with permission from Elsevier.) The proposed sequence of events (1) concentration of iron and copper increase in the cortex with aging. There is an overproduction of APP and AP in an attempt to suppress cellular metal-ion levels. (2) Hyper-metallation of AP occurs which may facilitate H202 production. (3) Hyper-metallated AP reacts with H202 to generate oxidized and cross-linked forms, which are liberated from the membrane. (4) Soluble AP is released from the membrane and is precipitated by zinc which is released from the synaptic vesicles. Oxidized AP is the major component of the plaque deposits. (5) Oxidized AP initiates microglia activation. (6) H202 crosses cellular membranes to react with Cu and Fe, and generate hydroxyl radicals which oxidize a variety of proteins and lipids.

Cherny, R.A. (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits P-amyloid accumulation in Alzheimer s disease transgenic mice. Neuron, 30, 665-676. 

Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI. 2001. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer s disease transgenic mice. Neuron 30 665-676. 

Boom A, Pochet R, Authelet M, Pradier L, Borghgraef P, Van Leuven F, Heizmann CW, Brion JP. 2004. Astrocytic calcium/zinc binding protein S100A6 over expression in Alzheimer s disease and in PS1/APP transgenic mice models. Biochim Biophys Acta 1742(1—3) 161—168. 

House E, CoUingwood J, Khan A, Korchazkina O, Berthon G, Exley C (2004) Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer s disease. J Alzheimers Dis 6 291-301... 

Abstract Multiple studies over the past 25 years have demonstrated alterations of zinc (Zn) in the brain in Alzheimer s disease (AD), although the potential foie of these alterations in the pathogenesis of AD remains unclear. The following examines normal and abnormal roles of Zn and Zn transport (ZIP and ZnT) proteins in brain and the potential effects of their alterations in the pathogenesis of AD. 

Deibel MA, Ehmann WD, Markesbery WR (1996) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer s disease possible relation to oxidative stress. J Neurol Sci 143 137-142... 

Markesbery WR, Ehmann WD (1994) Trace element alterations in Alzheimer s disease. In Terry RD, Katzman R (eds) Alzheimer s disease. Raven Press, New York, NY Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63 38-46 McMahon RJ, Cousins RJ (1998) Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc Natl Acad Sci U S A 95 4841 846... 

Rulon LL, Robertson JD, Lovell MA, Deibel MA, Ehmann WD, Markesber WR (2000) Serum zinc levels and Alzheimer s disease. Biol Trace Elem Res 75 79-85 Samudralwar DL, Diprete CC, Ni BF, Ehmann WD, Markesbery WR (1995) Hemenfeil imbalances in the olfactory pathway in Alzheimer s disease. J Neurol Sci 130 139-145 Segal D, Ghana E, Besser L, Hershfinkel M, Moran A, Sekler I (2004) A role for ZnT-1 in regulating cellular cation influx. Biochem Biophys Res Commun 323 1145-1150... 

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 el76. doi 10.1038/ cddis. 2011.57... 

FIGURE 21.9 Models of zinc and copper in the glutamatergic synapse in health and in Alzheimer s disease (a) the healthy synapse (b) Alzheimer s disease synapse. (From Duce Bush 2010. Copyright 2010 with permission from Elsevier.)... 

Cuajungco, M.R and Eaget, K.Y. 2003. Zinc takes the center stage Its paradoxical role in Alzheimer s disease. Brain Res. Brain Res. Rev. 41 44-56 Dahlgren, K.N., Manelli, A.M., Stine, W.B., Jn, Baker, L.K., Krafft, G.A. and LaDu, M.J. 2002. OUgomeric and fibrillar species of amyloid-P peptides differentieilly affect neuroneil viabUity. J. Biol. Chem. 277 32046-32053... 

The metal ion homeostasis is severely deregulated in Alzheimer s disease (Ehmann et al. 1986, Thompson etal. 1988, Samudralwar etal. 1995, Deibel et al. 1996, Cornett et al. 1998, Lovell et al. 1998). Increased concentrations of copper, iron, and zinc were detected in the neuropil of the brain where they were highly concentrated within amyloid plaques and reached concentrations up to 0.4 (jM (Cu) and 1 fM (Fe and Zn) (Smith et al. 1997, Lovell 1998). A hkely reason is that Ap binds equimolar amounts of Cu(II) and Zn(II) at pH 7.4 (Bush et al. 1993, 1994, Huang et al. 1997, Atwood et al. 1998). The amyloid precursor protein is a transmembrane glycoprotein that undergoes extensive alternative sphcing (Sandbrink etal. 1994) and has been shown to bind Zn(II) and Cu(II) at two distinc sites (Bush etal. 1993, Hesse etal. 1994). Experimentally induced disturbances of the homeostasis of Zn(II) and Cu(II) affect the metabo-hsm of the amyloid precursor protein (Borchardt et al. 1999, 2000). 

Cherny, R., Atwood, CS., Xilinas, ME., Gray, DN., Jones, WD., McLean, CA., Bamham, KJ., Volitakis, I., Fraser, FW., Kim, Y., Huang, X., Goldstein, LE., Moir, RD., Lim, JT.., Beyreuther, K., Zheng, H., Tanzi, RE., Masters, CL., Bush AI., Treatment with copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer s disease transgenic mice. Neuron, 2001.30(3) p. 641-642. 

The lack of zinc can also be a problem in biological systems and is responsible for disease states. For example, nitric oxide-dependent apoptosis can be induced in motor neurons by zinc-deficient SOD, and in some cases of amyotrophic lateral sclerosis, zinc-deficient SOD may participate in this type of oxidative mechanism involving nitric oxide.969 One form of hereditary human hair loss or alopecia was mapped to a specific gene and a mutation found in affected individuals. The gene encodes a single zinc finger transcription factor protein with restricted expression in the brain and skin.970 Zinc has been implicated in Alzheimer s via beta amyloid formation, and a role has been attributed for the cerebral zinc metabolism in the neuropathogenesis of Alzheimer s disease.971... 

In many crucial biological processes, such as oxygen transport, electron transport, intermediary metabolism, metals play an important part. Therefore, disorders of metal homeostasis, metal bioavailability or toxicity caused by metal excess, are responsible for a large number of human diseases. We have already mentioned disorders of iron metabolism (see Chapter 7) and of copper metabolism (see Chapter 14). The important role, particularly of redox metals such as copper and iron, and also of zinc, in neurodegenerative diseases, such as Parkinson s disease, Alzheimer s disease, etc. has also been discussed (see Chapter 18). We will not further discuss them here. 

Trace metals have been measured in various tissues by ICP-MS to investigate Alzheimer s disease [249-252]. Various sample preparation and processing approaches have been used, including flow injection analysis and extraction. Al, Si, and Sn levels were reported to be higher than in healthy tissue, whereas zinc and selenium concentrations were lower. In the temporal cortex there were also reductions of cesium and cerium concentrations. The mechanisms responsible and the key elements remain incompletely understood. 

P SS NMR was found to be useful to demonstrate the relationships between peptides, lipid membranes and metal ions.103 104 Such methodology is developed with intention to understand the mechanism of Alzheimer s disease. Disruption of the membrane structure by /1-amyloid in the presence of metal ions suggests the crucial role of such cations as Zn2+ and Cu2+. Metal ions alone have a different impact on the lipid membrane. Zinc induces weak motions on the lipid head-groups, which results in a slight decrease in 31P CSA. Adding the paramagnetic copper ions can cause total disruption of the lipid membrane to form smaller... 

Coleman PD, Flood DG (1987) Neuron numbers and dendritic extent in normal aging and Alzheimer s disease. Neurobiol Aging 8 521-545 Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ (2001) Alzheimer s disease amyloid-beta binds copper tmd zinc to generate an allosterically ordered membrane-penetrating structure conteiining superoxide dismutase-Uke subunits. J Biol Chem 276 20466-20473... 

Zinc and Zinc Transport and Sequestration Proteins in the Brain in the Progression of Alzheimer s Disease... 

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