Karen E. Duff, PhD

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Overview

Academic Appointments

  • Professor of Pathology and Cell Biology (in Psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Dr. Karen Duff has worked on Alzheimer's disease for more than 15 years, first creating transgenic mouse models of the disease, then testing therapeutic approaches to treating the disease in the mouse models. Lately, her lab has started looking at other neurodegenerative diseases including Tauopathies and Parkinson's disease.

Dr. Duff's work on AD was honored with the 2006 Potamkin Prize.

Email: ked2115@cumc.columbia.edu

Gender

  • Female

Credentials & Experience

Education & Training

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

Honors & Awards

Potamkin Prize 2006

Research

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.

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


 

TAUOPATHY IN AD AND FTD - MOLECULAR DETERMINANTS OF PHENOTYPIC DIVERSITY (Federal Gov)

Sep 30 2017 - Jun 30 2022

TAU PROPAGATION AND PROTEASOME MEDIATED CLEARANCE. (Private)

Jul 1 2017 - Jun 30 2020

ENTORHINAL-HIPPOCAMPAL CIRCUIT DYSFUNCTION IN AD MICE (Federal Gov)

Aug 1 2015 - Mar 31 2020

THE IMPACT OF SURGERY-INDUCED NEUROINFLAMMATION ON TAU PATHOLOGY AND FUNCTION (Federal Gov)

Feb 1 2016 - Jan 31 2020

INVESTIGATING THE MECHANISM OF APOE4-ASSOCIATED NEURONAL HYPERACTIVITY IN THE ENTORHINAL CORTEX AND ITS EFFECT ON TAUOPATHY PROPAGATION (Private)

Jan 15 2018 - Jan 14 2019

IMPACT OF TAU STRAINS ON PHENOTYPE DIVERSITY IN FTD (Private)

Sep 5 2017 - Sep 4 2018

PROPAGATION OF TAUOPATHY AND UPS DYSFUNCTION: IMPACT AND RESCUE WITH A UPS ACTIVATOR (Private)

Mar 1 2017 - Feb 28 2018

TESTING PHOSPHODIESTERASE (PDE) INHIBITORS FOR PROTEASOME FUNCTION (Private)

Nov 10 2015 - Nov 9 2017

METABOLOMIC/LIPIDOMIC ANALYSIS OF APOE ISOFORM EFFECTS IN AD-LINKED BRAIN REGIONS (Federal Gov)

Sep 15 2014 - Sep 14 2017

PROPAGATION OF TAUOPATHY: IMPACT ON CELLULAR PATHWAYS IN VIVO AND IN VITRO (Private)

Apr 20 2017 - Jul 20 2017

INVESTIGATING THE MECHANISM OF ENTORHINAL CORTEX HYPERMETABOLISM IN APOE4 TARGETED REPLACEMENT MICE (Private)

May 23 2016 - May 22 2017

PROPAGATION OF TAUOPATHY: ROLE OF DEGENERATION AND IMPACT OF IMMUNOTHERAPY (Federal Gov)

Aug 1 2013 - Apr 30 2017

AUTOPHAGIC CLEARANCE OF ABERRANT TAU: BIOCHEMICAL AND THERAPEUTIC IMPLICATIONS (Federal Gov)

May 1 2011 - Apr 30 2017

SPATIO TEMPORAL RELATIONSHIP OF PATHOLOGY AND FUNCTIONAL DECLINE WITH TAUOPATHY (Federal Gov)

Feb 1 2011 - Mar 31 2017

METABOLOMIC/LIPIDOMIC ANALYSIS OF APOE ISOFORM EFFECTS (Private)

Jul 1 2014 - Jun 30 2016

METABOLITE PROFILING TO IDENTIFY AD-RELEVANT PATHWAYS AFFECTED BY APOE VARIANTS (Federal Gov)

Sep 1 2014 - Apr 30 2016

CONFORMATION-DEPENDENT UPTAKE AND SECRETION OF TAU (Private)

Jul 1 2012 - Jun 30 2014

PROFILING PATHOLOGICALLY NORMAL APOE VARIANTS TO IDENTIFY PA THWAYS FOR AD (Federal Gov)

Sep 30 2010 - Jun 30 2013

EFFICACY OF TAU DEPLOYMERIZING AGENTS ORGANOTYPIC CULTURE SY STEM (Private)

Jul 1 2010 - Dec 31 2011

TAU AND NEURODEGENERATION II- A THERAPEUTIC TARGET (Federal Gov)

Jun 1 2007 - May 31 2011

PATHOLOGICAL AND FUNCTIONAL IMPACT OF TAUOPATHOLOGY IN VIVO (Federal Gov)

Jan 1 2009 - Jun 30 2010

Selected Publications

  • 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
  • Khan UA, Liu L, Provenzano FA, Berman DE, Profaci CP, Sloan R, Mayeux R, Duff KE, Small SA. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nature neuroscience. 2014; 17(2):304-11.
  • Clelland JD, Read LL, Drouet V, Kaon A, Kelly A, Duff KE, Nadrich RH, Rajparia A,Clelland CL. Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association. Schizophrenia research. 2014; 156(1):15-22.
  • Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE.Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nature medicine. 2016; 22(1):46-53.
  • Fu H, Hussaini SA, Wegmann S, Profaci C, Daniels JD, Herman M, Emrani S, Figueroa HY, Hyman BT, Davies P, Duff KE. 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice. PloS one. 2016; 11(7):e0159463.
  • Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW,Cook C, Fu H, Boonen RA, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE. Neuronal activity enhances tau propagation and tau pathology in vivo. Nature neuroscience. 2016; 19(8):1085-92.
  • Abounit S, Wu JW, Duff K, Victoria GS, Zurzolo C. Tunneling nanotubes: A possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases. Prion. 2016; 10(5):344-351.
  • Wang S, Kugelman T, Buch A, Herman M, Han Y, Karakatsani ME, Hussaini SA, Duff K,Konofagou EE. Non-invasive, Focused Ultrasound-Facilitated Gene Delivery for Optogenetics. Scientific reports. 2017; 7:39955.
  • Kim J, Choi IY, Duff KE, Lee P. Progressive Pathological Changes in Neurochemical Profile of the Hippocampus and Early Changes in the Olfactory Bulbs of Tau Transgenic Mice (rTg4510). Neurochemical research. 2017; 42(6):1649-1660. NIHMSID: NIHMS877837 PubMed
  • Fu H, Rodriguez GA, Herman M, Emrani S, Nahmani E, Barrett G, Figueroa HY,Goldberg E, Hussaini SA, Duff KE. Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease. Neuron. 2017; 93(3):533-541.e5.
  • Nuriel T, Angulo SL, Khan U, Ashok A, Chen Q, Figueroa HY, Emrani S, Liu L, Herman M, Barrett G, Savage V, Buitrago L, Cepeda-Prado E, Fung C, Goldberg E, Gross SS, Hussaini SA, Moreno H, Small SA, Duff KE. Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology. Nat Commun. 2017 Nov 13;8(1):1464. doi: 10.1038/s41467-017-01444-0. PubMed PMID: 29133888.

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. Arch Neurol. 2012 10:1-7. PMID: 23228982
  • Walker LC, Diamond MI, Duff KE, Hyman BT. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol. 2013 70(3):304-10. PMID: 2359992
  • Proceedings of the AMNI meeting. Nature Drug Discovery Reviews