Karen E. Duff, PhD

Departments And Divisions

  • Department of Pathology & Cell Biology
  • Department of Psychiatry
    Division of Integrative Neuroscience
  • Professor of Pathology and Cell Biology (in Psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)
Karen E. Duff, <span>PhD</span>

In general, we are exploring what goes wrong in the brains of patients with neurodegenerative diseases, especially Alzheimer’s disease (AD) and Frontal Temporal lobe Degeneration linked to tauopathy (FTD-tau) with the overall aim of identifying therapeutic approaches that may be beneficial for the treatment, or prevention of these diseases. Given our broad interest in neurodegenerative disease etiology and the insights to be gained by studying different diseases my lab has created various mouse models for the study of AD (amyloid accumulation), tauopathies and synucleinopathies. These models have facilitated the study of many aspects of pathogenesis from how the disease propagates through the brain, to imaging studies allowing the examination of structural and functional changes in the brain in living animals, to the identification of relevant druggable pathways and the testing of drugs. Our current interests are fourfold: the propagation of disease through the brain; the impact of ApoE4 on disease risk; the impact and restoration of functional clearance mechanisms; and the basis and manipulation of memory deficits using optogenetic and brain stimulation techniques

There are currently four projects underway in the lab.

1). One recent undertaking is to identify new pathways impacted by ApoE genotype that might explain why inheritance of ApoE4 allele increases risk for AD using a multi-omics approach (transcriptomics, lipidomics and metabolomics) on the same, pathology free human or ApoE targeted mouse brain tissue.

2). As the brains of AD patients often show multiple pathologies and accumulate several different types of potentially neurotoxic misfolded proteins including Abeta, tau, synuclein and TDP-43, we are currently focused on understanding the role of misfolded protein clearance pathways (mainly autophagy and UPS clearance) in disease etiology. In addition, as clinical trials using Abeta immunotherapy have suggested that reducing Abeta/amyloid in mild-moderate AD patients has no effect on their tauopathy, which continues to propagate, it would seem that drugs aimed at clearing all misfolded protein types from the brain would be beneficial.

3). It also seems likely that we will need to intervene very early in the disease, perhaps prophylactically, and at this time, very little is known of disease initiation and the earliest stages of propagation as most of the animal models that we, and others have generated do not accurately model the spatial and temporal sequence of the disease. Our more recent work modeling AD tauopathy using wild-type genomic (BAC derived) tau constructs has aimed to more faithfully replicate spatio-temporal aspects of tauopathy in AD, and current work aims to explore cellular and circuit vulnerability that defines a particular neurodegenerative disease. We have recently created a line of mice that models the earliest Braak stages of AD, when tauopathy is restricted to the entorhinal cortex (EC) and hippocampus. These mice, and a parallel line that expresses APP are being studied for spatial and temporal correlations of pathology and functional outcomes. One of the most significant findings from the mice so far is that tauopathy can spread through the brain along synaptically connected networks, and the observation that tau molecules can be transmitted from cell to cell, in vivo.  Using fMRI imaging, we have shown that dysfunction can spread to downstream brain regions, and that Abeta can potentiate the toxicity of tau expressed in the EC. Understanding the mechanisms involved in propagation, the impact on anatomically connected circuits and the relationship to functional decline determined by functional imaging and cognitive performance are the major directions for the lab.

4). We have a new project underway to look at the neurobiology of memory and learning and how it becomes dysfunctional in AD and FTD. This project also aims to look at how increasing neural activity may be harnessed to prevent cognitive decline, or even improve memory recall.

    Education & Training

  • PhD, 1991 Molecular genetics, Cambridge University (United Kingdom)

Lab Locations

  • Presbyterian Hospital Building (PH)

    630 West 168th Street
    Taub, 12-461
    New York, NY 10032
    Phone:
    (212) 305-8790
    Email:
    ked2115@cumc.columbia.edu

Honors & Awards

Potamkin Prize 2006

Research Interests

  • Pathogenic Mechanisms in Neurodegenerative Diseases
  • Neurobiology of Disease
  • Neurobiology of Learning and Memory
  • Molecular and Cellular Biology of Neurodegeneration
  • Synapses and Circuits

Grants


 

Publications

  • Mullan, M., Houlden, H., Windelspect, M., Fidani, L., Lombardi, C., Diaz, P., Rossor, M., Crook, R., Hardy, J., Duff, K. and Crawford, F. (1992) A locus for familial early onset Alzheimer’s disease on the long arm of Chromosome 14, proximal to a1-antichymotrypsin. Nature Genetics 2: 340-342.
  • Houlden, H., Collinge, J., Kennedy, A., Newman, S., Rossor, M., Lannfelt, L., Lilius, L., Winblad, B., Crook, R., Duff, K. and Hardy J. (1993) ApoE genotype and Alzheimer’s disease. Lancet: 342, 737-738.
  • Houlden, H., Crook, R., Duff, K., Collinge, J., Roques, P., Rossor, M. and Hardy, J. (1993) Confirmation that the apolipoprotein E4 allele is associated with late onset familial Alzheimer’s disease. Neurodegen. 2 283-286.
  • Duff, K., Kornblat, K., Wragg, M., Brown J., and Goate A. (1993). A novel AC repeat polymorphism in the amyloid precursor protein gene on chromosome 16. Mouse Genome.
  • Brown, J., Gydesen, S., Sorensen, S.A., Brun, A., Duff, K., Houlden, H., Fidani, L., Kulkarni, S., Cummings, J., Goate, A., Rossor, M. and Hardy J. (1993) Exclusion mapping in familial dementia. Dementia 4: 163-166.
  • Rempfer, R., Crook, R., Houlden, H., Duff, K., Hutton H., Roberts, G.W., Raghavan, R., Perry, R. and Hardy, J.(1994) Parkinson’s disease, but not Alzheimer's disease, Lewy body variant shows an association with mutant alleles at the cytochrome P450 (CYP2D6) gene. Lancet 344 815.
  • Duff K., McGuigan A., Huxley C., Schulz F. and Hardy J. (1994) Insertion of a pathogenic mutation into a yeast artificial chromosome containing the human amyloid precursor protein gene. Gene Therapy 1 71-75.
  • Crook. R., Hardy, J., and Duff, K. (1994) Single day ApoE genotyping. J. Neurosci Meths. 53, 125-1
  • Duff, K., and Hardy J. (1995) AD Mouse model made. Nature 373, 476-477.
  • Clark, R.F., Hutton, M., Fuldner, R.A. and colleagues. (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset ad families. Nature Genetics, 11219-222.
  • Perez-Tur, J., Froelich, S., Prihar, G., Crook, R., Baker, M., Duff, K., Wragg, M., Busfield, F., Clark, R., Roques, P., Fuldner, R.A., Johnston, J., Cowburn, R., Forsell, C., Axelman, K., Hardy, J., Goate, A., Lannfelt, L., and Hutton, M. (1995) A mutation in Alzheimer’s disease destroying a splice acceptor site in the presenilin 1 gene. NeuroReport 7, 204-207.
  • Hutton, M., Busfield, F., Wragg M. and colleagues. (1996) A complete analysis of the presenilin 1 gene in a series of families with Alzheimer’s disease with a mean onset below 60 years: identification of further mutations. NeuroReport, 7, 801-805
  • Houlden, H., Crook, R., Duff, K., Hutton, M., Collinge, J., Roques, P., Rossor, M. and Hardy, J. (1995) Absence of genetic association between the alpha-2-macroglobulin locus and late onset, familial Alzheimer’s Disease. Neurosci Letts. 88, 202-204.
  • Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C.M., Perez-tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M.N., Holcomb, L., Refolo, L., Zenk, B., Hardy, J. and Younkin, S. (1996) Increased amyloid-b42(43) in brains of mice expressing mutant presenilin 1. Nature 383 710-713.
  • Wragg, M., Hutton, M., Talbot, C. and colleagues. (1996) Association between a presenilin polymorphism and late onset Alzheimer's disease. Lancet 347, 509-512.
  • Prihar, G., Fuldner, R. Perez-Tur, J., Lincoln, S.J., Duff, K., Crook, R.J. Hardy, J., Philips, C.A., Venter, C., Talbot, C., Clark, R.F., Goate, A., Li, J., Potter, H., Karran, E., Roberts, G.W., Hutton, M. and Adams, M.D. (1996) The structure and alternate splicing of the presenilin 2 gene. NeuroReport 7, 1680-1684.
  • Ward, R.V., Davis, J.B., Gray, C.W. Bresciani, L.G., Caivano, M., Duff, K., Hutton, M., Hardy, J., Roberts, G. and Karran, E.H. (1996) Cleavage of presenilin-1 within cells by “presenilinase”. Neurodegeneration. 5, 293-98.
  • Barton, A.J.L., Crook, B.W., Karran, E.H., Brown, F., Dewar, D., Mann, D.M.A., Pearson, R.C.A., Graham, D.I., Hardy, J., Hutton, M., Duff, K., Goate, A.M., Clark, R.F. and Roberts, G.W. (1997) Alteration in brain presenilin-1 mRNA expression in early onset familial Alzheimer’s disease. Neurodegeneration 5, 213-218
  • Holcomb L, Gordon M, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada C, Eckman C, Younkin S, Hsiao K, Duff K. (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nature. Med, 4; p.97,
  • Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, Younkin S, Duff K, Hardy J, Hutton M (1998) Increased Abeta 42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol; 43: 256-8
  • T-P Wong, T. Debeir, K. Duff, and A.C Cuello. (1999) Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1, and amyloid precursor protein transgenes J. Neuroscience, 19 (7) 2706-2716
  • Bengley J, Duan W, Chan S, Duff K and Mattson M. (1999) Altered calcium homeostasis and mitocondrial dysfunction in cortical synaptic compartments of PS1 mutant mice. J. Neurochem, 72 (3) 1030-1039
  • Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M (1999) 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem.; 274:15134-4
  • McGowan E, Sanders S, Iwatsubo T, Takeuchi A, Saido T, Zehr C, Yu X, Uljon, S.E., Wang R, Mann D, Dickson D, Duff K. (1999) Amyloid phenotype characterization of transgenic mice over-expressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol. Dis 6, 231-244
  • H. Steiner, K. Duff, A. Capell, H. Romig, M. G.Grim, S. Lincoln, J. Hardy, X. Yu, M. Picciano, K. Fechteler, M. Citron, R. Kopan, B. Pesold, S. Keck, M. Baader, T. Tomita, T. Iwatsubo, R. Baumeister, and C. Haass (1999) A loss of function mutation of presenilin 2 interferes with amyloid b peptide production and notch signaling. J Biol Chem, 274: 28669-73
  • Wright K, Morgan D, Yu, X, Goss J, Salbaum M, Duff K and Gordon M. (1999) Mice transgenic for a human amyloid precursor protein promoter-lacZ reporter construct. J Mol Neurosci.13:111-20.
  • Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D (1999). Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet; 29: 177-85
  • J. Lewis, E. McGowan, J. Rockwood, H. Melrose, P. Nacharaju, K. Gwinn-Hardy, M. Murphy, M. Baker, John Hardy, X. Yu, K. Duff, A. Corral, W-L Lin, S-H Yen, D. Dickson, P. Davies, M. Hutton. (2000) Neurofibrillary tangles, amyotrophy, and progressive motor disturbance in tau mutant (P301L) transgenic mice. Nat Genet 4: 402-5
  • A Takeuchi, T. Saido, D. Mann, K. Hsiao, K. Duff and T. Iwatsubo. (2000) Lack of neuronal loss associated with age-related Ab deposition in the neocortices of transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid precursor protein. Am J Pathol 157(1): 331-9
  • Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M, Burki K, Davies P. (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol. Dis, 7, 87-98
  • Barrow PA, Empson RM, Gladwell SJ, Anderson CM, Killick R, Yu X, Jefferys JG, Duff K (2000) Functional Phenotype in Transgenic Mice Expressing Mutant Human Presenilin-1. Neurobiol Dis. 7, 119-26
  • L. Refolo, M. Pappolla, B. Malester, J. LaFrancois, R. Wang, G. Tint, K. Sambamurti, T. Bryant-Thomas and K. Duff. (2000) Hypercholesterolemia accelerates amyloid pathology in a transgenic mouse model for Alzheimer’s disease amyloidosis. Neurobiol Dis; 7(4): 321-31
  • B. Wengenack, S. Whelan, G.L. Curran, K. Duff and J.F. Poduslo. (2000) Quantitative Histological Analysis of Alzheimer’s Amyloid Deposition in APP, PS1 Transgenic Mouse. Neuroscience 101(4): 939-44
  • D. Morgan, D. Diamond, P. Gottschall, K. Ugen, C. Dickey, J. Hardy, K. Duff, P. Jantzen, G. DiCarlo, D. Wilcock, K. Connor, J. Hatcher, C. Hope, M. Gordon and G. Arendash (2000). Peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature, 408: 982-985
  • Matsuoka, Y, Malester B, Picciano, M, O'Banion K, Duff K (2001). Inflammatory response to amyloid deposition in transgenic mice over-expressing both mutant Amyloid Precursor Protein and Presenilin 1 Transgenes. Am J Path. 158 (4):1345-54
  • Hernandez D, Sugaya K, Qu T, McGowan E, Duff K, McKinney M. Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid precursor protein mutant genes. Neuroreport 2001;12 (7):1377-84
  • Matsuoka Y, Malester B, Picciano M, Duff K. (2001). Oxidative damage in response to the formation of fibrillar, but not diffuse amyloid in a transgenic model. Neuroscience, 104, 609-613.
  • Y. Matsuoka, M. Vila, S. Lincoln, A. McCormack, M. Picciano, J. LaFrancois, X. Yu, D. Dickson, W. Langston, E. McGowan, M. Farrer, J. Hardy, K. Duff, S. Przedborski, D. Di Monte (2001) Lack of Nigral Pathology in Transgenic Mice Expressing Human -Synuclein driven by the Tyrosine Hydroxylase Promoter. Neurobiol. Dis, 8:535-9.
  • L. Refolo, M. Pappolla, B. Malester, J. LaFrancois, R. Wang, G. Tint, K. Sambamurti, T. Bryant-Thomas and K. Duff. (2001) Drug-induced hypocholesterolemia retards amyloid pathology in a transgenic mouse model for Alzheimer’s disease Neurobiol Dis, 8:890-9.
  • G. Curran, T. Wengenack, S. Whelan, B. Malester, K. Duff, J. Poduslo (2001). Permeability of proteins at the blood-brain barrier in the double transgenic mouse model of Alzheimer’s disease. Neurobiol Dis;8:555-67.
  • Le R, Cruz-Cruz L, Urbanc B, Hsiao-Ashe K, Duff K, Irizarry MC, Stanley HE and Hyman BT (2001). Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer’s disease: implications for neural system disruption. J Neuropathol Exp Neurol.; 60:753-8.
  • M.A. Kurt, D.C. Davies, M. Kidd, K. Duff, S.C. Rolph, K.H. Jennings, D.R. Howlett (2001). Neurodegenerative changes associated with beta-Amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Exp Neurol.;171:59-71.
  • H Zheng, H. Xu, R. Wang , SN Uljon, J. Simpkins, LM Refolo, S. Petanceska, K. Duff (2002). Modulation of beta-amyloid accumulation by estrogen in AD mouse models J Neurochem ;80(1):191-6
  • Lee HJ, Zhang Y, Zhu C, Duff K, Pardridge WM (2002). Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Abeta peptide radiopharmaceutical. J Cereb Blood Flow Metab; 22 : 223-31
  • Urbanc B, Cruz L,, Le R, Sanders J, Hsiao-Ashe K, Duff K, Stanley HE, Irizarry MC and Hyman BT. (2002). Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer’s disease. PNAS, 99:13990-5
  • Y. Matsuoka, M. Saito, J. LaFrancois, M. Saito, K. Gaynor, V. Olm, L. Wang, E. Casey, Y. Lu, C. Lemere, K. Duff. (2003). Novel therapeutic approach for the treatment of AD using agents active in the periphery J. Neurosci, 23:29-33.
  • Lemere CA, Spooner ET, LaFrancois J, Malester B, Mori C, Leverone JF,Matsuoka Y, Taylor JW, DeMattos RB, Holtzman DM, Clements JD, Selkoe DJ, Duff KE. (2003) Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice. Neurobiol Dis.; 14: 10-8
  • Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P. (2003). Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem.; 86: 582-90.
  • Burns MP, Noble WJ, Olm V, Gaynor K, Casey E, LaFrancois J, Wang L, Duff K. (2003) Co-localization of cholesterol, apolipoprotein E and fibrillar Abeta in amyloid plaques. Brain Res Mol Brain Res.; 110: 119-25
  • W. Noble, V. Olm, K. Takata, E. Casey, M. O, J. Meyerson, K. Gaynor, J. LaFrancois, L. Wang, T. Kondo, P. Davies, M. Burns, Veeranna, R. Nixon, D. Dickson, Y. Matsuoka, M. Ahlijanian, L-F Lau, K. Duff (2003). Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 22; 38:555-65.
  • Wadghiri Y, Siggurdsson E, Sadowski M, Elliott J, Li Y, Sholztzova H, Tang CY, Agunaldo G, Pappolla M, Duff K, Wisneiwski T, Turnbull D. (2003). Detection of Alzheimer’s amyloid in transgenic mice using magnetic resonance microimaging, Magnetic Resonance in Medicine 50, 293-302
  • M. Burns, V. Olm, K. Gaynor, M. Mercken, J. LaFrancois, L. Wang, W. Noble, Y. Matsuoka and K. Duff. (2003) Presenilin redistribution associated with abberant cholesterol transport enhances b-amyloid production in vivo. J Neurosci. 23:5645-9.
  • Baslow MH, Suckow RF, Gaynor K, Bhakoo KK, Marks N, Saito M, Saito M, Duff K, Matsuoka Y, Berg MJ. (2003) Brain damage results in down-regulation of N-acetylaspartate as a neuronal osmolyte. Neuromolecular Med.; 3: 95-104
  • Petanceska SS, DeRosa S, Sharma A, Diaz N, Duff K, Tint SG, Refolo LM, Pappolla M.(2003). Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol. J Mol Neurosci.; 20: 395-406
  • Kurt MA, Davies DC, Kidd M, Duff K, Howlett DR. (2003). Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1transgenes. Neurobiol Dis.; 14: 89-97
  • Julia Tsai, Jaime Grutzendle, Karen Duff, Wen-Biao Gan (2004). Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181-3.
  • Klein RL, Lin WL, Dickson DW, Lewis J, Hutton M, Duff K, Meyer EM, King MA. (2004). Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol ;164: 347-53
  • Lemere C, Spooner E, LaFrancois J, Malester B, Mori C, Leverone J, Matsuoka Y, DeMattos R, Holzman D, Clements J, Selkoe D, Duff K (2004). Evidence of peripheral clearance of Abeta protein following chronic, active Ab immunization in PSAPP mice. Neurobiology of disease ;14:10-18.
  • Siggurdsson E, Wadghiri Y, Elliott J, Pappolla M, Duff K, Turnbull D, Wisneiwski T. (2004). Detection of Alzheimer’s amyloid by magnetic resonance imaging. Magnetic Resonance in Medicine; 50:293-302.
  • C. Saura, S-Y Choi, S. Malkani, B Shankaranarayana Rao, X. Sun, S. Chattarji, K. Duff, A. Kirkwood and J. Shen (2004). Synaptic dysfunction and age-dependent neurodegeneration caused by loss of presenilin function in the adult brain, Neuron; 42:23-36.
  • Burns MP, Duff K. (2004). Brain on steroids resists neurodegeneration. News and Views. Nat Med.;10: 675-6.
  • Kowa H, Sakakura T, Matsuura Y, Wakabayashi T, Mann DM, Duff K, Tsuji S, Hashimoto T, Iwatsubo T. (2004). Mostly Separate Distributions of CLAC- versus Abeta40- or Thioflavin -Reactivities in Senile Plaques Reveal Two Distinct Subpopulations of beta-Amyloid Deposits. Am J Pathol.; 165: 273-81.
  • Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, Muro A, Baralle F, Li H, Duff K, Szyf M, Cuello AC (2004). Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J Alzheimers Dis; 209-19.
  • Sadowski M, Pankiewicz J, Scholtzova H, Ji Y, Quartermain D, Jensen CH, Duff K, Nixon RA, Gruen RJ, Wisniewski T. (2004). Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol.; 63:418-28.
  • Horikoshi Y, Sakaguchi G, Becker AG, Gray J, Duff K, Aisen PS, Yamaguchi H, Maeda M, Kinoshita N, Matsuoka Y. (2004). Development of Abeta terminal end-specific antibodies and sensitive ELISA for Abeta variant. Biochem Biophys Res Commun.; 319: 733-7.
  • Helpern JA, Lee SP, Falangola MF, Dyakin VV, Bogart A, Ardekani B, Duff K, Branch C, Wisniewski T, de Leon MJ, Wolf O, O'Shea J, Nixon RA. (2004). MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease. Magn Reson Med.; 51: 794-8.
  • Lee SP, Falangola MF, Nixon RA, Duff K, Helpern JA. (2004). Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents. Magn Reson Med.52: 538-44.
  • Cataldo AM, Peterhoff CM, Schmidt SD, Terio NB, Duff K, Beard M, Mathews PM, Nixon RA. (2004). Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. (2004) J Neuropathol Exp Neurol. 63(8):821-30.
  • J. Helpern, S-P Lee, M. Falangola, V. Dyakin, A. Bogart, B. Ardekani, K. Duff, C. Branch, T. Wisniewski, M. de Leon, O. Wolf, J. O’Shea, J. R. Nixon (2004). MRI assessment of Neuropathology in a Transgenic Mouse Model of Alzheimer’s Disease. Magnetic resonance in Medicine; 51: 794-798.
  • E Planel and K Duff. (2005). Untangling memory deficits. NatMed;11(8):826-7.
  • W. Noble, E. Planel, C. Zehr, V. Olm, J. Meyerson, F. Suleman, K. Gaynor, L. Wang, J. LaFrancois, B. Feinstein, M. Burns, P. Krishnamurthy, Y Wen, R. Bhat, J. Lewis, D. Dickson and K. Duff. (2005). Inhibition of GSK-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci ;102(19):6990-5
  • Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA. (2005). Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol. 171(1):87-98.
  • Soreghan, B. A., Lu, B-W, Thomas, S. N., Duff, K, Rakhmatulin, E. A., Nikolskaya, T., Chen, T., and Yang, A. J. Using proteomics and network analysis to elucidate the consequences of synaptic protein oxidation in a PS1+AbetaPP mouse model of Alzheimer's disease. J. Alz Dis. 8; 227-41
  • Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A, Duff K, Bennett DA, Claudio Cuello A. (2005). The amyloid pathology progresses in a neurotransmitter-specific manner. Neurobiol Aging. 27(11):1644-57
  • Falangola MF, Ardekani BA, Lee SP, Babb JS, Bogart A, Dyakin VV, Nixon R, Duff K, Helpern JA. (2005). Application of a non-linear image registration algorithm to quantitative analysis of T(2) relaxation time in transgenic mouse models of AD pathology. J Neurosci Methods; 144(1): 91-7.
  • Falangola MF, Lee SP, Nixon R, Duff K, Helpern JA. (2005). Histological co-localization of iron in Abeta plaques of PS/APP transgenic mice. Neurochem Res. 30: 201-5.
  • C. Andorfer, C. Acker, Y. Kress, P. Hof, K. Duff and P. Davies. (2005). Cell Cycle Re-entry and Cell Death In Transgenic Mice Expressing Non-Mutant Human Tau Isoforms. J. Neurosci 25(22):5446-54.
  • Matsuoka Y, Shao L, Debnath M, Lafrancois J, Becker A, Gray A, Aisen P, Mathis C, Klunk W, Duff K. 2005. An Abeta sequestration approach using non-antibody Abeta binding agents. Curr. Alzheimer Res. 2.2 (2005): 265-68.
  • S. Kumar-Singh, D. Pirici, S. Serneels, E. McGowan, C. Ceuterick, J. Hardy, K. Duff, D. Dickson and C. Van Broeckhoven (2005). Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer’disease are centered on vascular walls Am J Pathol. 167:527-43
  • M. Burns, U. Igbavboa, L. Wang, W. Gibson Wood, K. Duff and W. Rebeck (2006). The effects of ABCA1 on cholesterol efflux and A[beta] levels in vitro and in vivo J. Neurochem. 98(3):792-800.
  • M. Burns, U. Igbavboa, L. Wang, W. Gibson Wood and K. Duff (2006). Distribution of cholesterol, but not total levels correlates with altered APP processing in statin treated mice. Neuromolecular Med. 8(3): 319-28.
  • Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M, Yu WH, Luchsinger JA, Wadzinski B, Duff KE, Takashima A (2007). Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J. Neurosci. 27(50): 13635-48.

Last 5 Years

  • Gray AJ, Sakaguchi G, Shiratori C, Becker AG, LaFrancois J, Aisen PS, Duff K, Matsuoka Y (2007). Antibody against C-terminal Abeta selectively elevates plasma Abeta. Neuroreport. 18(3): 293-6.
  • Planel E, Richter KE, Nolan CE, Finley JE, Liu L, Wen Y, Krishnamurthy P, Herman M, Wang L, Schachter JB, Nelson RB, Lau LF, Duff KE (2007). Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J. Neurosci. 27(12): 3090-7.
  • Falangola MF, Dyakin VV, Lee SP, Bogart A, Babb JS, Duff K, Nixon R, Helpern J. (2007) Quantitative MRI reveals aging-associated T2 changes in mouse models of Alzheimer's disease. NMR Biomed. 20(3): 343-51.
  • A. Cole, W. Noble, L. van Aalten, H. Yoshida, F. Plattner, D. Hogan, M. Taylor, F. Gunn-Moore, A. Verkhratsky, S. Oddo, F.La Ferla, K. Duff, M. Goedert, K. P. Giese, K. T. Dineley, D. Hanger, S. Allan and C. Sutherland. (2007) Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J. Neurochem. 103(3): 1132-44.
  • Hirata-Fukae, C., Li, H. F., Hoe, H. S., Gray, A. J., Minami, S. S., Hamada, K., Niikura, T., Hua, F., Tsukagoshi-Nagai, H., Horikoshi-Sakuraba, Y., Mughal, M., Rebeck, G. W., LaFerla, F. M., Mattson, M. P., Iwata, N., Saido, T. C., Klein, W. L., Duff, K. E., Aisen, P. S., & Matsuoka, Y. (2008). Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Res, 1216, 92-103.
  • Liu, L., Orozco, I. J., Planel, E., Wen, Y., Bretteville, A., Krishnamurthy, P., Wang, L., Herman, M., Figueroa, H., Yu, W. H., Arancio, O., & Duff, K. (2008). A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis, 31(1), 46-57.
  • Muhammad, A., Flores, I., Zhang, H., Yu, R., Staniszewski, A., Planel, E., Herman, M., Ho, L., Kreber, R., Honig, L. S., Ganetzky, B., Duff, K., Arancio, O., & Small, S. A. (2008). Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation. Proc Natl Acad Sci U S A, 105(20), 7327-7332.
  • Wen, Y., Planel, E., Herman, M., Figueroa, H. Y., Wang, L., Liu, L., Lau, L. F., Yu, W. H., & Duff, K. E. (2008). Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci, 28(10), 2624-2632.
  • Wen, Y., Yu, W. H., Maloney, B., Bailey, J., Ma, J., Marie, I., Maurin, T., Wang, L., Figueroa, H., Herman, M., Krishnamurthy, P., Liu, L., Planel, E., Lau, L. F., Lahiri, D. K., & Duff, K. (2008). Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron, 57(5), 680-690.
  • Yu, W. H., Matsuoka, Y., Sziraki, I., Hashim, A., Lafrancois, J., Sershen, H., & Duff, K. E. (2008). Increased dopaminergic neuron sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in transgenic mice expressing mutant A53T alpha-synuclein. Neurochem Res, 33(5), 902-911.
  • Yuan, A., Kumar, A., Peterhoff, C., Duff, K., & Nixon, R. A. (2008). Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci, 28(7), 1682-1687.
  • Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE: (2008) Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo, J Neurosci, 8:12798-12807
  • Liu L, Duff K: (2008) A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse, J Vis Exp (21). pii: 960. doi: 10.3791/960.
  • Small SA, Duff K: Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis (2008). Neuron, 60:534-542
  • Congdon EE, Duff KE: (2008). Is tau aggregation toxic or protective? J. Alzheimers Dis 14:453-457
  • Choi JJ, Wang S, Brown TR, Small SA, Duff KE, Konofagou EE. (2008) Noninvasive and transient blood-brain barrier opening in the hippocampus of Alzheimer's double transgenic mice using focused ultrasound. Ultrason Imaging. 30(3):189-200.
  • A. Kwan. G. Gouras, K. Duff and W. Web. (2009) Optical diagnosis of Alzheimer’s disease via multiphoton excited intrinsic fluorescence and second harmonic generation. Opt Express. 2;17(5):3679-89.
  • E. Planel, L. Liu, M. Herman, A. Bretteville, H. Figueroa, W-H Yu, P. Davies, D. Dickson and K. Duff. (2009) Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. FASEB J. 23(8):2595-604
  • W-H Yu, BJ Dorado, HY Figueroa, L Wang, E Planel, MR Cookson, L Clark and K Duff. (2009) Metabolic state determines the efficacy of macroautophagy clearance of pathological oligomeric alpha-synuclein. Am. J. Pathol 175(2): 736-47
  • E. Chang, E. Congdon, N. Honson, K. Duff and J. Kuret (2009) Structure-activity relationship of cyanine tau aggregation inhibitors J. Med. Chem. 52(11):3539-47.
  • E. Congdon, Y. Figueroa, L. Wang, E. Chang, J. Kuret & K. Duff (2009). Inhibition of Tau Polymerization with Cyanine Dye C11. J. Biol Chem. 284(31):20830-9.
  • Area-Gomez E, de Groof AJ, Boldogh I, Bird TD, Gibson GE, Koehler CM, Yu WH, Duff KE, Yaffe MP, Pon LA, Schon EA (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am. J. Pathol. 175(5):1810-6.
  • M. Polydor, C. Acker, K. Duff, P. Castillo, and P. Davies (2010). Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci; 29 (34):10741-9.
  • O'Leary JC 3rd, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J 3rd, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA. (2010) Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegen. 5:45.
  • William J. Netzer., Craig Powell., Yi Nong, Jacqueline Blundell, Lili Wong, Karen Duff, Marc Flajolet, Paul Greengard (2010) Lowering b-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model. PLoS 1, 5(6):e10943.
  • T. Oliveira, R. Chan, H. Tian, A. Staniszewski, H. Zhang, L. Wang, T-W Kim, K. Duff, M. Wenk, O. Arancio, and G. Di Paolo (2010). Phospholipase D2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits. J. Neurosci ; 30 (49):16419-28
  • C. Dall’Armi, A. Hurtado-Lorenzo, H. Tian, E. Morel, A. Nezu, R. Chan, W-H Yu, K. Robinson, O. Yeku,, K. Duff, M. Frohman, M. Wenk, A. Yamamoto and G. Di Paolo. (2010) The Phospholipase D1 Pathway Modulates Macroautophagy Nat. Communications 1:142.
  • Loane DJ, Washington PM, Vardanian L, Pocivavsek A, Hoe HS, Duff KE, Cernak I, Rebeck GW, Faden AI, Burns MP. (2011) Modulation of ABCA1 by an LXR agonist reduces beta-amyloid levels and improves outcome after traumatic brain injury. J Neurotrauma. 28(2):225-36.
  • Kim SR, Ries V, Cheng HC, Kareva T, Oo TF, Yu WH, Duff K, Kholodilov N, Burke RE. (2011) Age and α-synuclein expression interact to reveal a dependence of dopaminergic axons on endogenous Akt/PKB signaling. Neurobiol Dis; 44(2):215-22
  • Alldred MJ, Duff KE, Ginsberg SD. (2011) Microarray analysis of CA1 pyramidal neurons in a mouse model of tauopathy reveals progressive synaptic dysfunction. Neurobiol Dis. 45(2):751-62
  • Chan RB, Oliveira TG, Cortes EP, Honig LS, Duff KE, Small SA, Wenk MR, Shui G, Di Paolo G. (2011) Comparative lipidomic analysis of mouse and human brain with Alzheimer's disease. J. Biol. Chem. 287(4):2678-88
  • E. Congdon, J.W. Wu, N. Myeku, Y. Figueroa, M. Herman, P.S. Marinec, J. Gestwicki, C. Dickey, W-H Yu & K. Duff. (2012) Phenothiazine Induces Autophagy And Attenuates Tauopathy in vitro and in vivo. Autophagy 8(4)
  • L. Liu, V. Drouet, J. W. Wu, M. P. Witter, S. A. Small, CL. Clelland and K. Duff.(2012) Trans-synaptic Spread of Tau Pathology in vivo. PLoS One 7(2).
  • Vanderweyde T, Yu H, Varnum M, Liu-Yesucevitz L, Citro A, Ikezu T, Duff K, Wolozin B.(2012) Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J Neurosci. 32(24):8270-83.
  • Klionsky et al. (2012) Guidelines for the use and interpretation of assays monitoring autophagy. Autophagy. 2012; 8(4):445-544.
  • Jessica W. Wu, Mathieu Herman, Li Liu, Sabrina Simoes, Helen Figueroa, Joshua I. Steinberg, Martin Margittai, Rakez Kayed, Chiara Zurzolo, Gilbert Di Paolo, Karen. E. Duff. (2013) Small misfolded tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem. 288(3):1856-70.
  • Yuan A, Kumar A, Sasaki T, Duff K, Nixon RA. Axonal Transport Rates in vivo are Unaltered in Htau Mice. J Alzheimers Dis. 2013 Jul 17. PMID: 23948900
  • Usman Khan, Li Liu, Frank Provenzano, Diego Berman, Caterina Profaci, Richard Sloan, Richard, Mayeux, Karen Duff*, Scott A. Small*. (joint corresponding). Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease (in press, Nature Neuroscience)

Under Consideration

  • N. Myeku, CL. Clelland, TA. Shaler, YH. Figueroa, M. Herman, SE. Kaiser, W-H Yu and KE. Duff. Declining protein quality control in tauopathy can be rescued by stimulation of proteasome activity leading to reduced Tau burden and improved cognitive performance in vivo. Neuron

Invited Reviews and Book Chapters

  • Hardy, J. and Duff, K. (1993) Heterogeneity in Alzheimer’s Disease. Annals of Medicine 25; 437-440
  • Lannfelt, L., Folkesson, R., Mohammed, A., Winblad, B., Hellgren, D., Duff, K. and Hardy, J. (1993)
  • Alzheimer’s disease: molecular genetics and transgenic animal models. Behavioural Brain Research. 57, 207-213
  • Duff K. (1994) Modeling Alzheimer’s Disease in transgenic animals. J. Florida Med. Assoc. 91, 625-628
  • Duff K. (1997) Transgenic mouse models of AD come of age, TINs 20, 279-280
  • Hardy J, Duff K, Gwinn-Hardy K, Perez-Tur J and Hutton M. (1998) Genetic dissection of Alzheimer’s disease and related dementia’s:amyloid and its relationship to tau. Nature Neuroscience 1(5), 355-358
  • Duff K. (1998) Transgenic models for Alzheimer's disease. Neuropathol Appl Neurobiol: 101-103
  • Duff K. (1998) Recent work on AD transgenics. In: Current opinion in Biotechnology 9(6): 561-564
  • Duff K. (1999) Curing amyloidosis: will it work in humans? TINs 22, 485-48
  • Gandy S and Duff K. (2000). Post-menopausal estrogen deprivation and Alzheimer’s disease. Ed. R. Tanzi Experimental Gerontology, 35(4): 503-511
  • Burns M, Duff K (2002). Cholesterol in Alzheimer's disease and tauopathy. Ann N Y Acad Sci. 977:367-75.
  • Burns M, Duff K (2003). Use of in vivo models to study the role of cholesterol in the etiology of Alzheimer's disease. Neurochem Res. 979-86.
  • Duff K. Transgenic and Animal Models of AD. 2005 Ed. K Davis (ACNP 5th generation of progress)
  • Duff K. Transgenic models of AD neuropathology (2005). In 2nd edition of Neurobiology of Alzheimer’s Disease. Ed. D Dawbarn and SJ Allen
  • Karen Duff, Pavan Krishnamurthy, Emmanuel Planel and Michael Hutton. (2006) Animal models of Tauopathy. In Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology. Eds. S Sisodia and R Tanzi. Springer
  • Karen Duff, Y. Haung Yu and Yi Wen. "Cdk5 and Neuregulin-1 Signaling". Cyclin-dependent kinase 5. Ed. Nancy Y. Ip and Li-Huei Tsai. 1st ed. Published by Springer US. 2008.
  • Congdon EE, Duff KE. Is tau aggregation toxic or protective? Alzheimers Dis. 2008;14 (4):453-7.
  • Trojanowski JQ, Duff K, Fillit H, Koroshetz W, Kuret J, Murphy D, Refolo L; Frontotemporal Dementia (FTD) Working Group on FTD Drug Discovery. New directions for frontotemporal dementia drug discovery. Alzheimer’s Dement. 2008;4 (2):89-93.
  • W-H Yu and K. Duff. Metabolism, autophagy and Neurodegeneration. In: Autophagy in the Nervous System Eds. Charleen Chu and Zhenyu Yue.
  • Walker LC, Diamond MI, Duff KE, Hyman BT. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 2013 70(3):304-10. PMID: 2359992
  • Walker LC, Diamond MI, Duff KE, Hyman BT. Mechanisms of Protein Seeding in Neurodegenerative Diseases. Arch Neurol. 2012 10:1-7. PMID: 23228982
  • Proceedings of the AMNI meeting. Nature Drug Discovery Reviews