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Michael R. Nichols
Dr. Nichols received his B.S. degree from Lindenwood College and Ph.D. from Purdue University. Prior to joining the UM-St. Louis faculty in Fall 2004, he completed a postdoctoral fellowship at the Mayo Clinic in Jacksonville, FL.
nicholsmic@umsl.edu
Office: B319
Phone: (314) 516-7345
Fax: (314) 516-5342
Research Interests
Protein assembly or aggregation is widely recognized as a significant contributing factor to a number of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and others. Remarkably, the proteins or peptides implicated in these diseases, while possessing different amino acid sequences, all self-assemble to form similar fibrillar structures termed amyloid. One such peptide is amyloid-β (Aβ), a 40-42-residue peptide and the primary component of the senile plaques found in AD brains. The leading hypothesis in AD research maintains that accumulation of aggregated Aβ is the primary cause of the disease.
One research area in my laboratory involves mechanistic studies of Aβ aggregation. Objectives include isolation and characterization of aggregation intermediates and investigation of conditions that influence aggregation.These studies utilize an array of biophysical techniques to probe mechanistic and structural questions.The other major research thrust in my laboratory addresses the question of how Aβ aggregates are detrimental to cells.One hypothesis is induction of a sustained inflammatory response causing the release of harmful cytokines such as tumor necrosis factor-α.We are studying these effects in monocyte/macrophage cells and smooth muscle cells with the goal of understanding the cause of the inflammatory response, how it relates to cell toxicity, and identification of novel ways to regulate cytokine release.
Atomic force microscopy images (5 um x 5 um) of Ab(1-42) fibrils (left) and SEC-purified fibrillar precursors (right)
Selected Publications
"Stability of early-stage amyloid-β(1-42) aggregation species,” K. A.Coalier, G. S. Paranjape, S. Karki, and M. R. Nichols, Biochimica et Biophysica Acta, 2013, 1834, 65
“Amyloid-β(1-42) protofibrils formed in modified artificial cerebrospinal fluid bind and activate microglia,” G .S. Paranjape, S. E. Terrill, L. K. Gouwens, B. M. Ruck, and M. R. Nichols, J Neuroimmune Pharmacol, 2012, 8, 312
"Saccharide conjugates for treatment of Endotoxemia," A.V. Demchenko, M. R. Nichols and S. Kaeothip, Sophon, PCT Int. Appl. 2012, WO 2012145392A220121026.
“A comparative first-principles study of structural and electronic properties among memantine, amantadine and rimantadine,” K. Middleton, G.P. Zhang, M.R. Nichols, and T.F. George, Mol Physics, 2012, 110, 685
“Isolated amyloid-β(1-42) protofibrils, but not isolated fibrils, are robust stimulators of microglia,” G.S. Paranjape, L.K. Gouwens, D.C. Osborn, and M.R. Nichols, ACS Chem Neurosci, 2012, 3, 302.
“Substituted tryptophans at amyloid-β(1-40) residues 19 and 20 experience different environments after fibril formation,” R. T. McDonough, G. Paranjape, F. Gallazi, and M. R. Nichols, Arch. Biochem. Biophys. 2011, 514, 27
“Development of LPS antagonistic therapeutics: synthesis and evaluation of glucopyranoside-spacer-amino acid motifs,” S. Kaeothip, G. Paranjape, S. E. Terrill, A. F. G. Bongat, M. L. D. Udan, T. Kamkhachorn, H. L. Johnson, M. R. Nichols and A. V. Demchenko, RSC Advances, 2011, 1, 83.
"Probing the amyloid-β(1-40) fibril environment with substituted tryptophan residues," J. C. Touchette, L. L. Williams, D. Ajit, F. Gallazi, and M. R. Nichols Arch Biochem Biophys, 2010, 494, 192.
"Amyloid-β(1-42) fibrillar precursors are optimal for inducing tumor necrosis factor-α production in the THP-1 human monocytic cell line,” D. Ajit, M. L. D. Udan, G. Paranjape, and M.R. Nichols, Biochemistry, 2009, 48, 9011.
"Oligomeric amyloid-β(1-42) induces THP-1 human monocyte adhesion and maturation,” N. R. Crouse, D. Ajit, M. L. D. Udan, and M. R. Nichols, Brain Res, 2009,1254, 109
"Toll-like receptors 2 and 4 mediate Aβ(1-42) activation of the innate immune response in a human monocytic cell line,” M. L. D. Udan, D. Ajit, N. R. Crouse, and M .R. Nichols, J Neurochem, 2008, 104, 524
"Amyloid-β aggregates formed at nonpolar interfaces differ from amyloid-ß protofibrils produced in aqueous buffers,” M. R. Nichols, M. A. Moss, D. K. Reed, J. H. Hoh, and T .L. Rosenberry, Microsc Res Tech, 2005, 67, 164
"Amyloid-ß protofibrils differ from amyloid-β aggregates induced in dilute hexafluoroisopropanol in stability and morphology,” M. R. Nichols, M. A. Moss, D. K. Reed, S. Cratic-McDaniel, J. H. Hoh, and T .L. Rosenberry, J Biol Chem, 2005, 280, 2471
"Rapid assembly of amyloid-β peptide at a liquid/liquid interface produces unstable β-sheet fibers," M. R. Nichols, M. A . Moss, D. K. Reed, J. H. Hoh, and T. L. Rosenberry,Biochemistry, 2005, 44, 165
"Nordihydroguaiaretic acid does not disaggregate β-amyloid(1-40) protofibrils but does inhibit growth arising from direct protofibril association," M. A. Moss, N. H. Varvel, M. R. Nichols, D. K. Reed, J. H. Hoh, and T. L. Rosenberry, Mol Pharmacol, 2004, 66, 592