Keith J. Stine, Chair
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Dr. Nichols received his B.S. degree from Lindenwood College and Ph.D. from Purdue University. Prior to joining UMSL in Fall 2004, he completed a postdoctoral fellowship at the Mayo Clinic in Jacksonville, FL. He was appointed Associate Chair in 2019.
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 and factor-α interleukin-1-β. We are studying these effects in microglial and monocyte/macrophage 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 these inflammatory pathways.
|(Left) Electron microscopy image (59k magnification) of isolated Aβ42 protofibrils. (Right) Binding of Aβ42 protofibrils (green) tp BV-2 microglia. Cell nuclei are shown in blue.|
″Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease,″ Y. Zhou, W. M. Song, P. S. Andhey, A. Swain, T. Levy, K. R. Miller, P. L. Poliani, M. Cominelli, S. Grover, S Gilfillan, M. Cella, T. K. Ulland, K. Zaitsev, A. Miyashita, T. Ikeuchi, M. Sainouchi, A. Kakita, D. A. Bennett, J. A. Schneider, M. R.Nichols, S. A. Beausoleil, J. D. Ulrich, D. M. Holtzman, M. N. Artyomov and M. Colonna, Nature Medicine 2020, 26, 131.
″Disentangling aggregation-prone proteins: a new method for isolating α-synuclein species, An Editorial Highlight for "A simple, versatile and robust centrifugation-based filtration protocol for the isolation and quantification of α-synuclein monomers, oligomers and fibrils: Towards improving experimental reproducibility in α-synuclein research," M. R. Nichols, J. Neurochem. 2020, 153, 7.
″Inflammatory mechanisms in neurodegeneration,″ M. R. Nichols, M-K. St-Pierre, A-C. Wendeln, N. J. Makoni, L. K. Gouwens, E. C. Garrad, M. Sohrabi, J. J. Neher, M-E Tremblay and C. K. Combs, J. Neurochem. 2019, 49, 562.
″Aβ42 Protofibrils Interact with and Are Trafficked through Microglial-Derived Microvesicles, ″ L. K. Gouwens, M. S. Ismail, V. A. Rogers, N. T. Zeller, E. C. Garrad, F. T. Amtashar, N. J. Makoni, D. C. Osborn and M. R. Nichols, ACS Chemical Neuroscience, 2018, 9, 1416
″The conformational epitope for a new Aβ42 protofibril-selective antibody partially overlaps with the peptide N-terminal region,″ B. A. Colvin, V. A. Rogers, J. A. Kulas, E. A. Ridgway, F. S. Amtashar, C. K. Combs and M. R. Nichols, J. Neurochem. 2017, 143, 736
″Amyloid-β42 protofibrils are internalized by microglia more extensively than monomers,″ L. K. Gouwens, N. J. Makoni, V. A. Rogers and M. R. Nichols, Brain Res., 2016, 1648, Part_A, 485.
″APP regulates microglial phenotype in a mouse model of Alzheimer's disease,″ G. D. Manocha, A. M. Floden, K. Rausch, J. A. Kulas, B. A. McGregor, L. Rojanathammanee, K. R. Puig, K. L. Puig, S. Karki, J. E. Porter and C. K. Combs, M. R. Nichols, D. C. Darland, J. Neuroscience, 2016, 36, 8471
″Aβ40 has a subtle effect on Aβ42 protofibril formation, but to a lesser degree than Aβ42 concentration, in Aβ42/Aβ40 mixtures,″ S. E. Terrill-Usery, B. A. Colvin, R. A. Davenport and M. R. Nichols, Arch. Biochem. Biophys. 2016, 597, 1.
″Saccharide conjugates,″ A. V. Demchenko, M. R. Nichols and S. Kaeothip, U.S. Pat. Appl. 2015, US 9120838 B2 20150901.
"Biophysical Comparison of Soluble Amyloid-β(1-42) Protofibrils, Oligomers, and Protofilaments,″ M. R. Nichols, B. A. Colvin, E. A. Hood, D. C. Osborn and S. E. Terrill-Usery, Biochemistry, 2015, 54, 2193.
"CD47 does not mediate amyloid-β(1-42) protofibril-stimulated microglial cytokine release,″ S. Karki and M. R. Nichols, Biochem Biophys Res Commun, 2014, 454, 209.
"Amyloid-β(1-42) protofibrils stimulate a quantum of secreted IL-1β despite significant intracellular IL-1β accumulation in microglia,” S.E. Terrill-Usery, M.J. Mohan, and M.R. Nichols, BBA-Mol Bas Dis, 2014, 1842, 2276
"The influence of gold surface texture on microglia morphology and activation,” Y.H. Tan, S.E. Terrill, G.S. Paranjape, K.J. Stine, and Nichols, M.R., Biomater Sci, 2014, 2, 110
"The influence of gold surface texture on microglia morphology and activation," Y. H. Tan, S. Terrill, G. S. Paranjape, K. J. Stine and M. R. Nichols, Biomat. Sci. 2014, 2, 110.
"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.