28 January 2010
Amsterdam – Investigators from the International Center for Biomedicine and the University of Chile, in collaboration with the Center for Bioinformatics of the Universidad de Talca, have discovered that two drugs, the benzimidazole derivatives lanzoprazole and astemizole, may be suitable for use as PET (positron emission tomography) radiotracers and enable imaging for the early detection of Alzheimer’s Disease. The study is published in the current issue of the Journal of Alzheimer’s Disease.
Lanzoprazole and astemizole specifically tag pathological oligomers of tau which form the core of neurofibrillary tangles (NFTs), a pathognomonic brain lesion in Alzheimer´s patients. Prof. Dr. R.B. Maccioni and Dr. Leonel Rojo, authors of the study commented, “Since neurofibrillary tangles are positively correlated with cognitive impairment, we propose that these drugs have great potential in PET neuroimaging for in vivo early detection of AD and in reducing the formation of NFTs. These studies, based on advanced proteomics and databases of molecular interactions, may help to find potential new drugs for early diagnosis and treatment of Alzheimer´s disease. The findings are the result of a long-standing research program supported by the Alzheimer´s Association-USA and Fondecyt, Chile to evaluate new drug candidates.” Technological applications of this discovery are being developed with the collaboration of VentureL@b of the Universidad Adolfo Ibañez.
Interestingly, lanzoprazole and astemizole, already approved for treatment of proton pump disorders and as an antihistamine respectively, specifically bind directly to aggregated variants of tau protein, paired helical filaments (PHFs) and NFTs in Alzheimer´s brains. Until now it has not been possible to detect these pathological brain structures in living Alzheimer´s patients. The only confirmation of the disease has been attained by postmortem neuropathological evaluation.
Dr. Maccioni and Dr. Rojo postulate that “This important discovery will provide the stepping stone for the development of new specific neuroimaging technologies based on PET radiotracers that monitor the formation and growth of NFTs in patients during the course of their lives.”
The interactions of lanzoprazole and astemizole with the anomalous tau aggregates were assessed by classical radioligand assays, combined with surface plasmon resonance, bioinformatic approaches and immunofluorescence studies on isolated PHFs and brain samples from Alzheimer’s cases. The affinity of these for tau aggregates was significantly higher than that of polymers of the amyloid-b peptide according to SPR analysis. This is relevant since senile plaques are abundant but not pathognomonic in AD patients. Immunochemical studies on PHFs from brains of AD patients and SPR studies confirm these findings. The capacity of all these drugs to penetrate the blood-brain barrier was confirmed by either in vitro studies using parallel artificial membrane permeability assays or in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain in mice.
Reference: Rojo, Leonel E., Jans Alzate-Morales, Iván N. Saavedra, Peter Davies and Ricardo B. Maccioni. Selective Interaction of Lansoprazole and Astemizole with Tau Polymers: Potential New Clinical Use in Diagnosis of Alzheimer's Disease. J Alzheimers Dis 19:2 (January 2010).
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NOTES FOR EDITORS
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ABOUT LEAD INVESTIGATOR, PROF DR R.B. MACCIONI
Prominent Alzheimer´s disease investigator Dr. Ricardo B. Maccioni, Professor of Neurological Sciences, Faculty of Medicine & Professor of Cellular and Molecular Biology, Faculty of Sciences, Director of the Laboratory of Cellular and Molecular Neurosciences, University of Chile, Director of the International Center for Biomedicine (ICC), was recently awarded the Prize for Scientific Research 2008 by the FEBA Foundation of the University of Chile Medical School. This award recognizes the most heavily cited papers according to Thomson Reuters Scientific (ISI).
Three major papers published by Dr. Maccioni in the Journal of Alzheimer´s Disease were instrumental in winning this award:
“Mild Cognitive Impairment and Alzheimer Patients Display Different Levels of Redox-Active CSF Iron." Lavados, Guillón, Mujica, Rojo, Fuentes and Maccioni (2008) J Alzheimers Dis 13, 225-232.
“The Damage Signals Hypothesis of Alzheimer´s Disease Pathogenesis.” Fernández, Rojo, Kuljis and Maccioni (2008) J Alzheimers Dis 14: 329-333.
“Tau Phosphorylation by cdk5 and Fyn in Response to Amyloid Peptide Aβ25 35: Involvement of Lipid Rafts." Hernández, Lee Sjoberg and Maccioni (2009) “J Alzheimers Dis 16: 149-156.
Dr. Maccioni, who was ranked among the seven Chilean scientists with the highest impact factor and h-index ,in a recent study on science productivity covering all research fields, has served as Associated Editor of the Journal of Alzheimer´s Disease and is co-author with George Perry of the recent book Current Hypotheses and Research Milestones in Alzheimer´s Disease.
ABOUT THE JOURNAL OF ALZHEIMER’S DISEASE
The Journal of Alzheimer's Disease (http://www.j-alz.com) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 5.101 according to Thomson Reuters' 2009 edition of Journal Citation Reports. The Journal is published by IOS Press (http://www.iospress.nl).
The Journal is led by two internationally acknowledged experts in the field.
Editor-in-Chief George Perry, PhD, Professor of Biology, Dean of College of Sciences, University of Texas at San Antonio, is distinguished as one of the top 20 Alzheimer's disease researchers with over 800 publications and one of the top 100 most-cited scientists in Neuroscience & Behavior. He currently serves as President of the American Association of Neuropathologists.
Editor-in-Chief Mark A. Smith, Ph.D., Professor of Pathology, Case Western Reserve University, is recognized as one of the world's top 100 Alzheimer's disease investigators according to a recent study published in the March 2009 issue of the Journal of Alzheimer’s Disease. He also serves as Executive Director of the American Aging Association.
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George Perry, PhD
Editor-in-Chief, Journal of Alzheimer's Disease
University of Texas at San Antonio, College of Sciences
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Mark A. Smith, PhD
Editor-in-Chief, Journal of Alzheimer's Disease
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