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/

  • @karchlab

  • 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:

Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TLS, Goate AM, Cruchaga C, Bateman RJ; Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer`s disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. doi: 10.1186/s13195-018-0392-9. PMID: 30021643

Li Z, Del-Aguila JL, Dube U, Budde J, Martinez R, Black K, Xiao Q, Cairns NJ; Dominantly Inherited Alzheimer Network (DIAN), Dougherty JD, Lee JM, Morris JC, Bateman RJ, Karch CM, Cruchaga C, Harari O. Genetic variants associated with Alzheimer`s disease confer different cerebral cortex cell-type population structure. Genome Med. 2018 Jun 8;10(1):43. doi: 10.1186/s13073-018-0551-4. PMID: 29880032

Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TLS, Miller TM, Karch CM, Bateman RJ. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018 May 16;98(4):861-864. doi: 10.1016/j.neuron.2018.04.035. No abstract available. PMID: 29772204

Karch CM, Wen N, Fan CC, Yokoyama JS, Kouri N, Ross OA, Höglinger G, Müller U, Ferrari R, Hardy J, Schellenberg GD, Sleiman PM, Momeni P, Hess CP, Miller BL, Sharma M, Van Deerlin V, Smeland OB, Andreassen OA, Dale AM, Desikan RS; International Frontotemporal Dementia (FTD)–Genomics Consortium, International Collaboration for Frontotemporal Dementia, Progressive Supranuclear Palsy (PSP) Genetics Consortium, and International Parkinson’s Disease Genomics Consortium. Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. JAMA Neurol. 2018 Jul 1;75(7):860-875. doi: 10.1001/jamaneurol.2018.0372. PMID: 29630712

Broce I, Karch CM, Wen N, Fan CC, Wang Y, Tan CH, Kouri N, Ross OA, Höglinger GU, Muller U, Hardy J; International FTD-Genomics Consortium, Momeni P, Hess CP, Dillon WP, Miller ZA, Bonham LW, Rabinovici GD, Rosen HJ, Schellenberg GD, Franke A, Karlsen TH, Veldink JH, Ferrari R, Yokoyama JS, Miller BL, Andreassen OA, Dale AM, Desikan RS, Sugrue LP. Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies. PLoS Med. 2018 Jan 9;15(1):e1002487. doi: 10.1371/journal.pmed.1002487. PMID: 29315334

Ridge PG, Karch CM, Hsu S, Arano I, Teerlink CC, Ebbert MTW, Gonzalez Murcia JD, Farnham JM, Damato AR, Allen M, Wang X, Harari O, Fernandez VM, Guerreiro R, Bras J, Hardy J, Munger R, Norton M, Sassi C, Singleton A, Younkin SG, Dickson DW, Golde TE, Price ND, Ertekin-Taner N, Cruchaga C, Goate AM, Corcoran C, Tschanz J, Cannon-Albright LA, Kauwe JSK; Alzheimer’s Disease Neuroimaging Initiative. Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer`s disease resilience. Genome Med. 2017 Nov 29;9(1):100. doi: 10.1186/s13073-017-0486-1. PMID: 29183403

Wang C, Ward ME, Chen R, Liu K, Tracy TE, Chen X, Xie M, Sohn PD, Ludwig C, Meyer-Franke A, Karch CM, Ding S, Gan L. Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. Stem Cell Reports. 2017 Oct 10;9(4):1221-1233. doi: 10.1016/j.stemcr.2017.08.019. Epub 2017 Sep 28. PMID: 28966121

Tcw J, Wang M, Pimenova AA, Bowles KR, Hartley BJ, Lacin E, Machlovi SI, Abdelaal R, Karch CM, Phatnani H, Slesinger PA, Zhang B, Goate AM, Brennand KJ. An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells. Stem Cell Reports. 2017 Aug 8;9(2):600-614. doi: 10.1016/j.stemcr.2017.06.018. Epub 2017 Jul 27. PMID: 28757165

Yokoyama JS, Karch CM, Fan CC, Bonham LW, Kouri N, Ross OA, Rademakers R, Kim J, Wang Y, Höglinger GU, Müller U, Ferrari R, Hardy J; International FTD-Genomics Consortium (IFGC), Momeni P, Sugrue LP, Hess CP, James Barkovich A, Boxer AL, Seeley WW, Rabinovici GD, Rosen HJ, Miller BL, Schmansky NJ, Fischl B, Hyman BT, Dickson DW, Schellenberg GD, Andreassen OA, Dale AM, Desikan RS. Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol. 2017 May;133(5):825-837. doi: 10.1007/s00401-017-1693-y. Epub 2017 Mar 7.
PMID: 28271184

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, Sassi C, Bras J, Gibbs RJ, 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 (ARUK) Consortium, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton A, Hardy J, Kamboh MI, George-Hyslop PS, Cairns N, Morris JC, Kauwe JSK, Goate AM. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer`s disease. Nature. 2014 Jan 23;505(7484):550-554. doi: 10.1038/nature12825. Epub 2013 Dec 11. PMID: 24336208

Last Updated: 7/27/2018 11:15:36 AM

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