Karen Hsiao Ashe, M.D., Ph.D.
Edmund Wallace and Anne Marie Tulloch
Chairs in Neurology and Neuroscience
Professor of Neurology and Neuroscience
Director, N. Bud Grossman Center for Memory Research and Care
Primary Hospital Affiliation: University of Minnesota Medical Center, Fairview
Year of Appointment: 1992
Medical School: Harvard Medical School, 1982
Graduate School: Massachusetts Institute of Technology, 1981
Residency: Medicine, University of California, San Francisco, 1982-1983; Neurology, University of California, San Francisco, 1983-1986
Email: hsiao005@umn.edu
Alzheimer's disease and aging: animal and cellular models.
Our research addresses the molecular basis of memory loss and cognitive dysfunction in Alzheimer's disease. The studies involve the creation of transgenic mouse models of Alzheimer's disease in order to understand how the amyloid-ß and tau proteins impair memory and cognition. The work has shown that the aggregates of amyloid-ß and tau proteins which define Alzheimer's disease neuropathologically do not cause cognitive deficits in mice. These investigations have led to the discovery of a form of the amyloid-ß protein called Aß star (Aß*) that disrupts cognitive function in mice and rats, and revealed a potential mechanism by which interactions with a neuronal receptor may impair memory.
Current Projects:
The predictive value of Aß* for Alzheimer's disease in the elderly. Cognitive function often declines with age and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals progress to develop Alzheimer's disease with neurodegeneration. There is a prodrome frequently referred to as Mild Cognitive Impairment (MCI) or CDR 0.5 in which individuals have subjective complaints, mild clinical abnormalities, some plaques and tangles, and neuronal loss generally restricted to the entorhinal cortex and the hippocampus. However, there is a large degree of overlap between the healthy non-demented cases (CDR 0) and the CDR 0.5 cases. Some individuals with CDR 0.5 have no overt loss of neurons, indicating that neuronal loss does not occur invariably prior to cognitive dysfunction. A similar argument applies to tau pathology and neuritic degeneration, where there is extensive overlap between CDR 0 and CDR 0.5 cases, arguing also against these features causing early cognitive symptoms. The discrepancies between neuropathology and cognitive function in individual cases cannot be explained on the basis of specific structural lesions in the brain. There is increasing evidence that the cognitive decline and pathological changes associated with Alzheimer's disease develop many years before the dementia can be diagnosed, blurring the boundary between age-related cognitive decline and the earliest stages of Alzheimer's disease. Poor performance on memory tests can predict Alzheimer's disease up to 15 years before it is diagnosed, and asymptomatic individuals at risk genetically for Alzheimer's disease have evidence of brain dysfunction in functional magnetic resonance imaging and positron emission tomography studies. Yet these tests cannot be used to predict the fate of individual subjects. We have shown that Aß* is present at higher levels in brain tissue from patients with Alzheimer's disease and MCI than in individuals without cognitive impairment. Whether Aß* can predict Alzheimer's disease in individuals with age-related cognitive decline and MCI is a focus of current studies.
Therapeutically targeting Aß* in mice and humans. A major effort in developing Alzheimer's disease modifying therapies has been directed at reducing the amyloid deposits in the brain. However, amyloid deposits correlate weakly with cognitive impairment in humans and do not cause memory deficits in mice, arguing for the existence of a special pool of Aß inducing cognitive disturbances. This critical pool of Aß remained elusive until the identification of Aß*. Because Aß* is the form of Aß that specifically disrupts cognitive function, therapeutic interventions aimed at blocking the detrimental effects of Aß* would ameliorate cognitive impairments directly. Potentially successful strategies include: 1) small molecules blocking the formation or action of Aß*; 2) small molecules promoting the clearance or degradation of Aß*; and 3) immune therapies against Aß*. Oral agents are more practical than ones that need to be given intravenously, like therapeutic monoclonals. Developing a safe, oral drug which counteracts Aß* is a focus of current efforts.
Identifying the form of the tau protein that impairs memory. The accumulation of insoluble aggregates consisting of proteins such as tau, huntingtin, prion protein, ataxin, and Aß occurs in many neurodegenerative disorders. These aggregates often define the disorders neuropathologically, but their relative contribution to disease symptoms compared to other, hypothetical, intermediate protein assemblies is controversial and the identity of the theoretical intermediates has been elusive. Our discovery that Aß* is responsible for memory loss in plaque-forming mice, and causes cognitive deficits when injected directly into healthy rats, sets a precedent for identifying other “star” proteins inducing brain dysfunction. We have shown that mice expressing a repressible human tau variant develop progressive age-related neurofibrillary tangles, neuronal loss and behavioral impairments. Following the suppression of transgenic tau, memory function recovers and neuron numbers stabilize but, surprisingly, tangles continue to accumulate. Thus, tangles are not sufficient to cause cognitive decline or neuronal death. Current work aims to identify the form of the tau protein called tau* impairing memory.Selected Publications:
A tale about Tau
K.H. Ashe; New England Journal of Medicine 357:933-5, 2007
A specific amyloid-ß protein assembly in the brain impairs memory
Sylvain Lesné, Ming Teng Koh, Linda Kotilinek, Rakez Kayed, Charles G. Glabe, Austin Yang, Michela Gallagher and Karen H. Ashe; Nature 440, 352-357 (16 March 2006) | doi:10.1038/nature04533; Received 23 November 2005; Accepted 13 December 2005
Tau suppression in a neurodegenerative mouse model improves memory function. [K. SantaCruz, J. Lewis, T. Spires, J. Paulson, L. Kotilinek, M. Ingelsson, A. Guimaraes, M. DeTure, M. Ramsden, E. McGowan, C. Forster, M. Yue, J. Orne, C. Janus, A. Mariash, M. Kuskowski, B. Hyman, M. Hutton, K.H. Ashe (2005) Science 309:476-81]
Natural oligomers of the amyloid-ß protein specifically disrupt cognitive function. [J. Cleary, D. M. Walsh, J.J. Hofmeister, G.M. Shankar, M.A. Kuskowski, D.J. Selkoe, K.H. Ashe (2005) Nature Neuroscience 8:79-84]
Reversible memory loss in a mouse transgenic model of Alzheimer' disease. [L. Kotilinek, B. Bacskai, M. Westerman, T. Kawarabayashi, L.H. Younkin, B.T. Hyman, S.G Younkin, K.H. Ashe (2002) Journal of Neuroscience 22:6331-6335]
The relationship between Aß and memory in the Tg2576 mouse model of Alzheimer's disease. [M. Westerman, D. Cooper-Blacketer, A. Mariash, L. Kotilinek, T. Kawarabayashi, L.H. Younkin, G. Carlson, S.G. Younkin, K.H. Ashe (2002) Journal of Neuroscience 22:1858-1867]
Learning and memory in transgenic mice modeling Alzheimer’s disease. [K.H. Ashe (2001) Learning and Memory 8:301-308]
Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. [P.F. Chapman, G.L. White, M.W. Jones, D. Cooper-Blacketer, V.J. Marshall, M. Irizarry, L.H. Younkin, M.A. Good, T.V.P. Bliss, B.T. Hyman, S.G. Younkin, K. Hsiao (1999) Nature Neuroscience 2:271-276]
Correlative memory deficits, Aß elevation, and amyloid plaques in transgenic mice. [K. Hsiao, P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, G. Cole (1996) Science 274:99-102]
Age related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. [K.K. Hsiao, D.R. Borchelt, K. Olson, R. Johannsdottir, R., C. Kitt, W. Yunis, S. Xu, C. Eckman, S. Younkin, D. Price, C. Iadecola, H.B. Clark, G. Carlson (1995) Neuron 15:1203 1218]