For over 20 years Dr. Karen H. Ashe has been engaged in the study of the molecular genetics, biochemistry and molecular biology of prion diseases and Alzheimer’s disease. Dr. Ashe's contributions are in three main areas: the genetics of human prion diseases; transgenic models of prion and Alzheimer’s diseases; and the molecular basis of memory loss in Alzheimer’s disease.
Dr. Ashe's lab created the Tg2576 transgenic mouse, which develops subtle memory problems and plaques composed of amyloid-beta protein. This mouse models the “pre-clinical” phase of Alzheimer’s disease. During this phase, the disease processes are underway in the brain, but people do not yet notice symptoms. This model of Alzheimer's disease is studied around the world today. The work continued with the creation of other mouse models of neurodegenerative disease, including developing the rTg4510 mouse that models another biological sign of Alzheimer's: neurofibrillary tangles made of tau protein.
1.) Finding markers in blood and cerebral spinal fluid that will let us
detect Alzheimer’s disease at its earliest stages, before people notice symptoms -- and before there is irreplacable loss of large numbers of brain cells.
2.) Creation of an improved mouse model of Alzheimer’s disease that more
completely recapitulates the course of the human disease, exhibiting plaques, tangles, memory loss, and massive death of brain cells.
3.) Increasing the understanding of the basic mechanisms of Alzheimer’s
disease at the molecular level so that an intervention in the process might be found to halt the progress of the disease, specifically focusing on
Abeta*56 and Tau.
4.) Translation of safe and affordable compounds which have shown
results in mouse models of Alzheimer’s disease into a prevention strategy to reduce the incidence of the disease in humans through a collaboration of laboratory and clinical researchers.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Liu P, Reed MN, Kotilinek LA, Grant MK, Forster CL, Qiang W, Shapiro SL, Reichl JH, Chiang AC, Jankowsky JL, Wilmot CM, Cleary JP, Zahs KR, Ashe KH. Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration. Cell Rep. 2015 Jun 23;11(11):1760-71.
Weitzner DS, Engler-Chiurazzi EB, Kotilinek LA, Ashe KH, Reed MN. Morris Water Maze Test: Optimization for Mouse Strain and Testing Environment. J Vis Exp. 2015 Jun 22;(100):e52706.
Liu P, Paulson JB, Forster CL, Shapiro SL, Ashe KH, Zahs KR. Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique β-Amyloid Oligomer Profile. PLoS One. 2015 May 6;10(5):e0126317.
Zahs KR, Ashe KH. More than a FAD: The In Vivo Effects of Disease-Linked Presenilin-1 Mutations. Neuron. 2015 Mar 4;85(5):893-5.
Zahs KR, Ashe KH. β-Amyloid oligomers in aging and Alzheimer's disease. Front Aging Neurosci. 2013 Jul 4;5:28.
Handoko M, Grant M, Kuskowski M, Zahs KR, Wallin A, Blennow K, Ashe KH. Correlation of specific amyloid-β oligomers with tau in cerebrospinal fluid from cognitively normal older adults. JAMA Neurol. 2013 May;70(5):594-9.
Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH. Brain amyloid-β oligomers in ageing and Alzheimer's disease. Brain. 2013 May;136(Pt 5):1383-98.
Ashe KH, Aguzzi A. Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion. 2013 Jan-Feb;7(1):55-9.
Liu P, Kemper LJ, Wang J, Zahs KR, Ashe KH, Pasinetti GM. Grape seed polyphenolic extract specifically decreases aβ*56 in the brains of Tg2576 mice. J Alzheimers Dis. 2011;26(4):657-66.
Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81.
Ashe KH, Zahs KR. Probing the biology of Alzheimer's disease in mice. Neuron. 2010 Jun 10;66(5):631-45.
Zahs KR, Ashe KH. 'Too much good news' - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer's disease? Trends Neurosci. 2010 Aug;33(8):381-9. Epub 2010 Jun 9.
Reed MN, Liu P, Kotilinek LA, Ashe KH. Effect size of reference memory deficits in the Morris water maze in Tg2576 mice. Behav Brain Res. 2010 Sep 1;212(1):115-20. Epub 2010 Apr 8.
Reed MN, Hofmeister JJ, Jungbauer L, Welzel AT, Yu C, Sherman MA, Lesné S, LaDu MJ, Walsh DM, Ashe KH, Cleary JP. Cognitive effects of cell-derived and synthetically derived Aβ oligomers. Neurobiol Aging. 2011 Oct;32(10):1784-94. Epub 2010 Jan 19.
Paulson JB, Ramsden M, Forster C, Sherman MA, McGowan E, Ashe KH. Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of Alzheimer's disease. Am J Pathol. 2008 Sep;173(3):762-72. Epub 2008 Jul 31.
Kotilinek LA, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A, Lesne S, Falinska A, Younkin LH, Younkin SG, Rowan M, Cleary J, Wallis RA, Sun GY, Cole G, Frautschy S, Anwyl R, Ashe KH. Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain. 2008; 131:651-64.
K.H. Ashe A tale about tau. New England Journal Medicine. 2007; 357:933-5.
Kotilinek LA, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A, Lesne S, Falinska A, Younkin LH, Younkin SG, Rowan M, Cleary J, Wallis RA, Sun GY, Cole G, Frautschy S, Anwyl R, Ashe KH. Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain. 2008 Mar; 131(Pt 3):651-64.
Ashe KH. In search of the molecular basis of memory loss in Alzheimer disease. Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):200-1.
Ashe KH. Molecular basis of memory loss in the Tg2576 mouse model of Alzheimer's disease. J Alzheimers Dis. 2006;9(3 Suppl):123-6.
Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT.
Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol. 2006 May;168(5):1598-607.
Lesne S, Koh MT, Sotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory.
Nature. 2006 Mar 16;440(7082):352-7.
Sylvain Lesné, Ming Teng Koh, Linda Kotilinek, Rakez Kayed, Charles G. Glabe, Austin Yang, Michela Gallagher, Karen H. Ashe. A specific amyloid- ß protein assembly in the brain impairs memory. Nature. 2006 Mar 16; 440 , 352-357.
Current Graduate Students:
Julia Gamache (Neuroscience, University of Minnesota).
Former Graduate Students:
Maureen Handoko (Ph.D. 2012, Neuroscience, University of Minnesota).
Carol Ma (Ph.D. 2006, Neuroscience, University of Minnesota).
Marcus Westerman (Ph.D. 2001, Neuroscience, University of Minnesota).