Room 209, Sanders-Brown Center On Aging
800 South Limestone Street
Lexington, KY 40536-0230
Molecular and Cellular Biochemistry
Neurodegeneration, Alzheimer’s disease
Irfan Baig, Ph. D. - Research Associate
Sergey Matveev , Ph.D. – Scientist II
We seek to elucidate the contribution of misfolded proteins to chronic neurodegenerative diseases and to contribute to the development of therapeutic agents capable of modifying the course of these diseases. Our focus is on the Alzheimer’s ß-peptide (Aß) and its role in the cognitive decline in Alzheimer’s disease.
Aβ Peptide and RAGE Interactions in AD– The Receptor for Advanced Glycation Endproducts (RAGE) binds multiple ligands associated with oxidative stress and impacts cellular signaling. We are using affinity chromatography and LC-MS proteomics to identify proteins that associate with the RAGE ligand-binding domain (sRAGE) in AD. The molecular details of the high affinity interaction of one of these ligands, soluble oligomers of the Aβ peptide, with sRAGE are being determined.
Small molecule inhibitors of soluble Aβ oligomer assembly– Soluble non-fibrillar oligomeric forms of Aβ are highly potent neurotoxins that disrupt synaptic function. A screen for small drug-like molecules that would inhibit oligomer formation has identified several chemical structural classes that inhibit oligomer assembly as well as additional classes that dissociate preformed Aβ oligomers. We are studying the mechanisms of compound action and will be seeking funding for med chem. optimization moving towards therapeutics.
Molecular Basis of PIB Binding in the AD Brain– Our studies with a compound used as an imaging agent for clinical PET studies to measure brain Aβ pathology, Pittsburgh Compound B (PIB), indicated that AD brain has a high density of binding sites for PIB while animal models of Aβ pathology including aged non-human primates have a very low density of PIB sites, even though they have similar amounts of Aβ pathology. We propose that the formation of this site holds key information as to why AD is a uniquely human disease. We are purifying the PIB binding site from AD brain to learn how it differs in the animal models. With the support of Bayer Healthcare we will be studying the potential for an amyloid ligand fingerprint unique to AD.
Phage Display and Biofluid PIB Binding as a Biomarker for AD– Phage display of peptide sequences that bind to targets analogous to the epitope recognition sequences in antibodies is a powerful technology that has advantages over antibodies including penetrating into target crevices and not requiring immunogenicity. In collaboration with Rodney Guttmann (Sanders-Brown) we are screening for M13 bacteriophage that recognize the PIB binding site in AD brain to use to detect PIB sites released into the CSF or blood.
Weidner, A. M., Housley, M., Murphy, M. P, and LeVine, III, H.“Purified High Molecular Weight Synthetic Aβ(1-42) and Biological Aβ Oligomers are of Comparable Potency in Rapidly inducing MTT Formazan Exocytosis”,Neurosci. Lett. in press.
Simons, L. J., Augelli-Szafran, C. E., Caprathe, B. W., Callahan, M., Graham, J. M., Kimura, T., Lai, Y., LeVine, III, H., Lipinski, W., Sakkab, A. T., Tasaki, Y., Walker, L. C., Yasunaga, T.,Ye, Y., Zhuang, N. “The Synthesis and Structure-Activity Relationship of Substituted N-Phenyl Anthranilic Acid Analogs as Amyloid Aggregation Inhibitors”, Bioorganic & Medicinal Chemistry Letters,19: 654-657 (2009). PMID: 19121939
LeVine, III, H. and Walker, L. C. “Molecular Polymorphism of Aβ in Alzheimer’s Disease Plaques”, Neurobiology of Aging,31: 542-548 (2010). doi:10.1016/j.neurobiolaging.2008.05.026. PMCID: PMC2842206 [Available on 2011/4/1]
Rosen, R. F., Walker, L. C., and LeVine, III, H.“PIB Binding in Aged Primate Brain: Unique Enrichment of High Affinity Sites in Humans with AD", Neurobiology of Aging32: 223-234 (2011). doi:10.1016/j.neurobiolaging.2009.02.011. PMCID: PMC2891164
LeVine, III, H., Ding, Q., Walker, J. A., Voss, R. S., and Augelli-Szafran, C. E. “Clioquinol and other hydroxyquinoline derivatives inhibit Aβ(1–42) oligomer assembly”, Neurosci. Lett. 465: 99-103 (2009). doi: 10.1016/j.neulet.2009.08.002. PMCID: PMC2754118
Murphy, M. P. and LeVine, III, H.,“Alzheimer’s Disease and the β-Amyloid Peptide”,J. Alzheimer’s Disease19(1): 311-323 (2010). PMCID: PMC2813509
Rosen, R. F., Ciliax, B. J., Gearing, M., Dooyema, J., Wingo, T. S., Lah, J. J., Ghiso, J., LeVine, III, H. Walker, L. C. “Deficient High-Affinity Binding of Pittsburgh Compound B in a Case of Alzheimer's Disease”, Acta Neuropathologica,119: (2) 221-233 (2010). PMID: 19690877
Bruce-Keller, A. J., Gupta, S., Parrino, T. E., Knight, A. G., Ebenezer, P. J., Weidner, A. M., LeVine, III, H., Keller, J. N., and Markesbery, W. R. “NOX Activity is Increased in Mild Cognitive Impairment”, Antioxidants and Redox Signaling,12(12): 1371-1382 (2010). PMCID: PMC2864654
Murphy, M. P., Morales, J., Beckett, C. L., Astarita, G., Piomelli, D.,Weidner, A., Studzinski, C. M., Dowling, A., L., S., Wang, X.,LeVine, III, H., Kryscio, R. J., Lin, Y., Barrett, E., and Head, E. “Changes in Cognition and Aβ Processing with Long Term Cholesterol Reduction using Atorvastatin in Aged Dogs”, J. Alzheimer’s Disease, 22: 135-150 (2010). PMID 20847439
Beckett, T. L., Niedowicz, D. M., Studzinski, C.M., Weidner, A. M., Webb, R. L., Holler, C. J., Ahmed, R. R., LeVine, III, H., and Murphy, M. P. “Effects of Nonsteroidal Anti-Inflammatory Drugs on Amyloid-β Pathology in Mouse Muscle”,Neurobiology of Disease, 39: 449-456 (2010). PMID 20493261
Abdul, H. A., Baig, I., LeVine, III, H., Guttmann, R. P., and Norris, C. M. “Calpain-mediated Proteolysis of Calcineurin is Increased in Hippocampus During Mild Cognitive Impairment and is Stimulated by Oligomeric Abeta”, Aging Cell,in press. doi: 10.1111/j.1474-9726.2010.00645.x. PMID 20969723
Ebenezer, P. J., Weidner, A. M., LeVine, III, H., Markesbery, W. R., Murphy, M. P., Zhang, Le, Dasuri, K., Fernandez-Kim, S. O., Bruce-Keller, A. J., Gavilán, E., and Keller, J. N. “Neuron specific toxicity of oligomeric beta amyloid: Implications for JUN-kinase and oxidative stress”,J. Alzheimer’s Disease, 22(3): 839-848 (2010). PMID 20858948
LeVine, III, H. Ch. 12.1 “Reporters of Amyloid Structure”,inProtein Reviews series, vol. 4Protein Misfolding, Aggregation, and Conformational Diseases, V. N. Uversky, and A. L. Fink (eds), pp. 287-302, Kluwer Academic / Plenum Publishers, 2006.
LeVine, III, H. and Walker, L. C. “Chapter 11. Models of Alzheimer’s Disease”,inHandbook of Models for Human Aging, Conn, P. M. (ed), pp. 121-134, Academic Press, Elsevier, New York, 2006.
LeVine, III, H. and Augelli-Szafran, C.E. “Chapter 4.5. Aβ Polymerization Reduction”inProtein Folding in Neurodegenerative Diseases: Mechanisms and Therapeutic Strategies, CRC Enzyme Inhibitors Series, H. John Smith, Claire Simons, and Robert D.E. Sewell (eds), pp. 209-231, CRC Press, Boca Raton, FL, 2008.
LeVine, III, H. “Ligand Imaging of Misfolded Proteins”,inProtein Misfolding Diseases: Current and Emerging Principles and Therapies, M. Ramirez-Alvarado, J. W. Kelly, and C. M. Dobson, (eds), John Wiley and Sons, Ch. 30, 647-671, 2010.
Walker, L. C., Rosen, R. F., andLeVine, III, H.“Chapter 8. Pathogenic Protein Strains as Diagnostic and Therapeutic Targets in Alzheimer's Disease”, inAlzheimer’s Disease:Targets for New Clinical Diagnostic and Therapeutic Strategies, Frontiers in Neuroscience Series, A. S. Rudolph and R. D. Wegrzyn (eds), CRC Press, Boca Raton, FL,in press.
LeVine, III, H. Genetic Engineering - A Reference Handbook, 264 pp., ABC-CLIO, Santa Barbara, CA, Second Edition, 346pp., August,2006.History, medical, technological, legislative, legal, and social impact of recombinant DNA technology, Social resources.
LeVine, III, H. Drug Discovery and Development-Technology In Transition (undergraduate textbook), with Hugh Rang (ed), (2006), England, 346 pp., Second Edition with R. G. Hill (ed), 2010, Churchill Livingstone/Harcourt Brace, London, England. –winner of 1st prize as Medical Book of the Year inthe 2006 Society of Authors/Royals Society of Authors Medical Book Competition, and also 1st prize in the Best Edited Book section. Highly Commended in the 2006 BMA Medical Books competition.
LeVine, III, H. Medical Imaging, 211 pp, Greenwood Press/ABC-CLIO, Santa Barbara, CA, 2010.Development and societal impact of medical imaging technologies from the discovery of the X-ray – Fluorography, CT, MRI, PET, SPECT.
LeVine, III, H. The Great Explainer: The Story of Richard Feynman, 144 pp., Morgan-Reynolds Publishing, Greensboro, NC, 2009.Biography of the quirky physicist who worked on the atomic bomb, won a Nobel Prize for atomic physics, explained the Challenger shuttle disaster, and played the bongos.