Celeste M. Karch, Ph.D.

Assistant Professor
Psychiatry
Neurology

Neurosciences Program
Molecular Cell Biology Program
Developmental, Regenerative and Stem Cell Biology Program

  • 314 747-3161

  • 8134

  • karchc@wustl.edu

  • https://karchlab.wustl.edu/

  • neurodegeneration, neurogenetics, Alzheimer`s disease, frontotemporal dementia, tau, amyloid precursor protein, induced pluripotent stem cells (iPSC), cell and molecular biology, molecular mechanisms

  • Understanding the molecular and cellular mechanisms underlying tauopathies

Research Abstract:

The goal of my research is to understand the molecular and cellular mechanisms underlying tauopathies. Tau dysfunction is implicated in many neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease. Most of these diseases are characterized by tau protein aggregation and are termed tauopathies. In these diseases, tau is affected at the molecular (splicing), protein (hyperphosphorylation, cleavage, aggregation), and cellular (secretion) levels. Thus, defining the molecular mechanisms underlying tauopathies will require unraveling the complexities of the MAPT gene that encodes the tau protein, tau protein dysfunction within the cell, and the cell-cell interactions that produce pathology in the human brain. First, we are working to define the common mechanism by which disease mutations and risk variants in the MAPT gene disrupt tau metabolism and contribute to disease pathology. Second, we are interested in defining the mechanisms by which disease mutations in PSEN1 and PSEN2, which cause familial Alzheimer’s disease, and novel risk variants in PLD3 and other recently identified genes disrupt Aβ, and in turn, alter tau metabolism. Third, we are exploring the role that neuronal subtype specific vulnerability plays in tauopathies. We use traditional immortalized cell models, mouse models and human brain tissue in combination with human induced pluripotent stem cell-derived neuron and astrocytes to answer these questions. Defining the molecular and cellular mechanisms underlying tauopathies will improve our basic understanding of tau biology and will inform novel avenues for therapeutic intervention.

Selected Publications:

Yokoyama JS, Wang Y, Schork AJ, Thompson WK, Karch CM, Cruchaga C, McEvoy LK, Witoelar A, Chen CH, Holland D, et al. Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease. JAMA Neurol. 2016 Jun 1;73(6):691-7. doi: 10.1001/jamaneurol.2016.0150. PubMed PMID: 27088644; PubMed Central PMCID: PMC4905783.

Wakle-Prabagaran M, Lorca RA, Ma X, Stamnes SJ, Amazu C, Hsiao JJ, Karch CM, Hyrc KL, Wright ME, England SK. BKCa channel regulates calcium oscillations induced by alpha-2-macroglobulin in human myometrial smooth muscle cells. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):E2335-44. doi: 10.1073/pnas.1516863113. Epub 2016 Apr 4. PubMed PMID: 27044074; PubMed Central PMCID: PMC4843459.

Karch CM, Ezerskiy L, Redaelli V, Giovagnoli AR, Tiraboschi P, Pelliccioni G, Pelliccioni P, Kapetis D, D`Amato I, Piccoli E, et al. Missense mutations in progranulin gene associated with frontotemporal lobar degeneration: study of pathogenetic features. Neurobiol Aging. 2016 Feb;38:215.e1-12. doi: 10.1016/j.neurobiolaging.2015.10.029. Epub 2015 Nov 2. PubMed PMID: 26652843; PubMed Central PMCID: PMC4738142.

Karch CM, Ezerskiy LA, Bertelsen S; Alzheimer’s Disease Genetics Consortium (ADGC), Goate AM. Alzheimer`s Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One. 2016 Feb 26;11(2):e0148717. doi: 10.1371/journal.pone.0148717. eCollection 2016. PubMed PMID: 26919393; PubMed Central PMCID: PMC4769299.

Kauwe JS, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL, Staley LA, Karch CM, Harari O, Cruchaga C, Ainscough BJ, Bales K, Pickering EH, Bertelsen S; Alzheimer`s Disease Neuroimaging Initiative, Fagan AM, Holtzman DM, Morris JC, Goate AM. Genome-wide association study of CSF levels of 59 alzheimer`s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet. 2014 Oct 23;10(10):e1004758. doi: 10.1371/journal.pgen.1004758. eCollection 2014 Oct. PubMed PMID: 25340798; PubMed Central PMCID: PMC4207667.

Karch CM, Cruchaga C, Goate AM. Alzheimer`s disease genetics: from the bench to the clinic. Neuron. 2014 Jul 2;83(1):11-26. doi: 10.1016/j.neuron.2014.05.041. Review. PubMed PMID: 24991952; PubMed Central PMCID: PMC4120741.

Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, Bertelsen S, Goate AM, Cruchaga C. Coding variants in TREM2 increase risk for Alzheimer`s disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. doi: 10.1093/hmg/ddu277. Epub 2014 Jun 4. PubMed PMID: 24899047; PubMed Central PMCID: PMC4189899.

Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M; UK Brain Expression Consortium, Hardy J, Ryten M, Trabzuni D, Weale ME, Ramasamy A, Smith C, Sassi C, Bras J, Gibbs JR, Hernandez DG, Lupton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K; Alzheimer’s Research UK Consortium, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, Kölsch H, Kehoe PG, Hooper NM, Vardy ER, Mann DM, Pickering-Brown S, Brown K, Kalsheker N, Lowe J, Morgan K, David Smith A, Wilcock G, Warden D, Holmes C, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton AB, Hardy J, Kamboh MI, St George-Hyslop P, Cairns N, Morris JC, Kauwe JS, Goate AM. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer`s disease. Nature. 2014 Jan 23;505(7484):550-4. doi: 10.1038/nature12825. Epub 2013 Dec 11. PubMed PMID: 24336208; PubMed Central PMCID: PMC4050701.

Last Updated: 6/29/2016 9:03:56 AM

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