Beta-amyloid toxicity

Ghanta J, Shen CL, Kiessling LL, Murphy RM. A strategy for designing inhibitors of beta-amyloid toxicity. J Biol Chem 1996 271 ... 

Sadler II, Smith DW, Shearman MS, Ragan Cl, Tailor VJ, Pollack SJ. Sulphated compounds attenuate beta-amyloid toxicity by inhibiting its association with cells. Neuroreport 1995 7 49-53. 

Kihara T, Shimohama S, Akaike A (1999) Effects of nicotinic receptor agonists on beta-amyloid beta-sheet formation. Jpn J Pharmacol 79 393-396 Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A (2001) alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem 276 13541-13546 Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, Maeda T, Akaike A (1998) Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res 792 331-334... 

Sadowski M, Pankiewicz J, Scholtzova H, Ripellino JA, Li Y, Schmidt SD, Matiiews PM, Fryer JD, Holtzman DM, Sigui dsson EM, Wisniewski T (2004) A syntiietic peptide blocking tire apolipoprotein E/beta-amyloid binding mitigates beta-amyloid toxicity and fibril foimation in viti o and reduces beta-amyloid plaques in ti ansgenic mice. Am J Patiiol 165 937—948. 

Kihara, T.. Shimohama, S., Sawada. H.. Kimura, J., Kume, T., Kochiyama, H. ct al., 1997. Nicotinic receptor stimulation protects neurons against beta-amyloid toxicity. Ann. Neurol. 42, 159-163. 

These synthesized compounds were found to be useful for rescuing cells from beta-amyloid toxicity and in the treatment of Alzheimer s disease. 

Bastianetto S, Quirion R (2002) EGb 761 is a neuroprotective agent against beta-amyloid toxicity. Cell Mol Biol (Noisy-le-Grand) 48(6) 693-697... 

Shin-Ya K, Kunigami T, Kim JS, Seto H. Protective effect of catechin against beta-amyloid toxicity in hippocampal neurons and PC12 cells. J Neurochem 1997 69 S42-S52. 

Roth AD, Ramirez G, Alarcon R, Von Bernhardi R. Oligodendrocytes damage in Alzheimer s disease beta amyloid toxicity and inflammation Biol Res. 2005 38(4) 381-387. 

An elucidation of the mechanisms of brain iron homeostasis, as outlined in figure 1, will help our understanding of AD especially since iron binds to Ap-peptide and enhances beta-amyloid toxicity [35-38]. Excess iron accumulation is a consistent observation in the AD brain. As discussed above, patients with hemochromatosis are at risk developing AD at an earlier age [2]. Brain autopsy samples from AD patients have elevated levels of ferritin iron, particularly in the neurons of the basal ganglia [39] and most amyloid plaques contain iron and ferritin-rich cells [40]. Clinically there is a reported decrease in the rate of decline in AD patients who were treated with the intramuscular iron chelator, desferrioxamine [41]. Iron enhances cleavage of the Ap-peptide domain of APP by the metalloprotease alpha secretase [42, 43]. Part of the protective effect of the major cleavage product of APP, APP(s), may derive from its capacity to scavange metals to diminish metal-catalyzed oxidative stress to neuronal cells [44]. APP is, itself, a metalloprotein [4]. 

Schubert, D. and M. Chevion, The role of iron in beta amyloid toxicity. Biochem Biophys Res Commun, 1995.216(2) p. 702-7. 

ROTH A, scHAFFNER w and BERTEL c (1999) Phytoestrogen kaempferol (3,4, 5,7-tetrahydroxyflavone) protects PC 12 andT47D cells from beta-amyloid-induced toxicity. JNeurosci Res. 57 (3) 399-404. 

Pallitto MM, Ghanta J, Heizelman P, Kiessling LL, Murphy RM. Recognition sequence design for peptidyl modulators of beta-amyloid aggregation and toxicity. Biochemistry 1999 38 3570-3578. 

Hertel, C., Terzi, E., Hauser, N., Jakob-Rotne, R., Seelig, J., and Kemp, J. A. (1997). Inhibition of the electrostatic interaction between beta-amyloid peptide and membranes prevents beta-amyloid-induced toxicity. Proc. Natl. Acad. Sd. USA 94, 9412-9416. 

Preston, J. P., Hipkiss, A. R., Himsworth, D. J. T., Romero, I. A., and Abbott, J. N. (1998). Toxic effects of beta-amyloid (25-35) on immortalised rat brain endothelial cells Protection by carnosine, homocarnosine and beta-alanine. Neurosci. Lett. 242,105-108. 

CS298 luvone, T., G. Esposito, R. Esposito, R. Santamaria, M. Di Rosa, and A. A. Izzo. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PCI2 cells. J Neurochem 2004 89(1) 134-141. CS299 Ng, R. S., D. A. Darko, and R. M. 

Yan JJ, Cho JY, Kim HS, Kim KL, Jung JS, Huh SO, Suh HW, Kim YH, Song DK. 2001. Protection against beta-amyloid peptide toxicity in vivo with long-term administration of ferulic acid. Br J Pharmacol 133 89-96. 

Behl C, Davis JB, Lesley R, Schubert D. 1994. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77 817-827. 

Gutierrez-Zepeda A, Santell R, Wu Z, Brown M, Wu Y, Khan I, Link CD, Zhao B, Luo Y. 2005. Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neurosci 6 54. 

While melatonin is not currently being used to treat these conditions, research is currently underway investigating its role in preventing Alzheimer s disease. A study published in Biochemistry in 2001 showed that melatonin can inhibit the development of amyloid beta, a toxic substance that has been linked to the development of Alzheimer s. Other studies suggest that melatonin may be helpful in reducing the side effects caused by medications that are used to treat schizophrenia. 

Bastianetto, S., Yao, Z.X., Papadopoulos, V., and Quirion, R., Neuroprotective effects of green and black teas and their catechin gallate esters against beta-amyloid-induced toxicity. Eur J Neurosci, Jan, 23(1), 55-64, 2006. 

Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-kapptiB in hippocampal synaptic plasticity. Synapse 35 151-159 Baltimore D (1988) Gene therapy intraceUular immunization. Nature 335 395-396 Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J et al (1995) Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 92 9328-9332... 

Furukawa, K., and Mattson, M.E. 1995. Cytochalasins protect hippocampal neurons against amyloid beta-peptide toxicity evidence that actin depolymerization suppresses Ca2+ influx. JNeurochem 65, 1061-1068. 

Qhr L, Liu Y, Cooper C, Liu B, Wilsorr B, Horrg IS (2002) Microglia enharrce beta-amyloid pepdde-mduced toxicity irr cor deal arrd meserrcephalic rreurorrs by produchrg reacdve oxygerr species. J Neurochem 83 973—983. 

In conclusion, lithium is a moderate inhibitor of GSK-3, which in pre-clinical studies has been shown to influence pathophysiological mechanisms of Alzheimer s disease, i.e. both decreasing the hyperphosphorylation of tau and reducing the metabolism of beta amyloid. However, the action of lithium is complicated by the diverse actions associated with this compound. Due to the toxic effects associated with long-term use of lithium and therapeutically higher concentrations to decrease GSK-3 activity, it may not be considered as a prime candidate for treatment of Alzheimer s disease. 

In summary, AR-A014418 is a potent and specific GSK-3 inhibitor capable of intervening with both tau phosphorylation and beta-amyloid-induced toxicity. AR-A014418 is also the only published specific GSK-3 inhibitor with documented in vivo efficacy consistent with an Alzheimer s disease modifying mode of action. Thus, AR-A014418 represents an important research tool to study the therapeutic potential of GSK-3 inhibition in neurological disease. 

Iversen LL, Mortishire-Sith RJ, Pollack SJ, Shearman MS (1995) The toxicity in vitro of beta-amyloid protein. Biochem J 311 1-16... 

McGeer and Rogers are willing to concede that p-amyloid can kill neurons directly, but they think that most of the damage is caused by the peptide s immunological effects, specifically, its ability to activate the complement cascade. Their unpublished results show that when immune factors are present, the toxicity of beta-amyloid jumps tremendously, says Rogers. 

Behl, C., Davids, J., Cole, G.M., and Schubert, D. (1992). Vitamin E protects nerve cells from amyloid beta — protein toxicity, Biochem. Biophys. Red Commun., 186, 994. 

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