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, Reichl JH, Rao ER, McNellis BM, Huang ES, Hemmy LS, Forster CL, Kuskowski MA, Borchelt DR, Vassar R, Ashe KH, Zahs KR. Quantitative comparison of dense-core amyloid plaque accumulation in amyloid-β protein precursor transgenic mice. J Alzheimers Dis. 2017;56(2):743-761.
- Zhao X, Kotilinek LA, Smith B, Hlynialuk C, Zahs K, Ramsden M, Cleary J, Ashe KH. Caspase-2 cleavage of tau reversibly impairs memory. Nat Med. 2016;22(11):1268-1276.
- Liu P, Reed MN, Kotilinek LA, Grant MK, Forster CL, Qiang W, Shapiro SL, Reichl JH, Chiang A, 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;11(11):1760-1771.
- 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):893-895.
- 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;70(5):594-599.
- 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;136(Pt 5):1383-98.
- Ashe KH, Aguzzi A. Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion. 2013;7(1):55-59.
- 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.
- 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;32(10):1784-1794.
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).