James Cleary Lab
Our research is focused on age-related neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The laboratory is primarily interested in detailed characterization of cognition deficits and memory losses that occur as these diseases progress. We develop sensitive bioassays to measure the cognitive changes seen in animal models of AD and PD. Recent efforts involve investigation of the several proteins, including amyloid beta peptide, tau-related protein, and alpha-synuclein in development of neurodegeneration and cognitive deficits in AD and PD. Recently, we have begun to develop a program for investigation of the relationship between brain injury, neurotoxic protein formation and cognitive deficits.
We employ transgenic animal models of progressive neurodegenerative disease and sophisticated cognitive assessment tools to assess the contributions of mutant proteins in neurodegenerative disease and to test potential therapeutic interventions. We characterize the behavior of these mouse models under several behavioral protocols, including those for motivation, attention, perception and memory. We track the cognitive changes over time and compare the neurodegeneration using biochemistry and immunohistochemistry.
Cognitive Dysfunction in Transgenic Mouse Model of Alpha-synucleinopathy
Sponsor: Department of Veterans Affairs Merit Award
Project Description: This project attempts to understand the neuropathological basis for dementia and cognitive deficits in Parkinson's disease (PD). Studies with human patients have shown that the presence of two proteins called alpha-synuclein (alpha-syn) and beta-amyloid (βA) are correlated with dementia in PD. Thus, we will use transgenic mouse models that recapitulate the major protein abnormalities seen in PD and PD dementia to investigate the contribution of these proteins to neurodegenerative processes. We will also carefully characterize the behavior and cognitive function of these mice and compare the results to the findings from the neurodegeneration studies. Finally, we will determine if environmental risk, which is relatively higher during military service, can adversely affect the course of PD-associated cognitive impairment long after the risk exposure.
Effects of Alzheimer's Disease-related Protein Conformations
Sponsor: Private Foundation
Project Description: Amyloid beta peptide (abeta) is the most likely natural protein toxin responsible for memory loss and neurodegeneration in Alzheimer's disease (AD). A few other closely associated protiens, tau and alpha-synuclein, may be influenced by abeta and may also contribute to neurodegeneration. The abeta peptide exists in several forms, from soluble species (monomers, dimers, etc) to very large aggregated fibril assemblies. Many recent studies, including several from our lab, suggest neither the monomers nor the large aggregates are responsible for the memory loss characteristic of AD. The current project attempts to further identify the particular amyloid species responsible for AD.
Walsh DM, Klyubin I, Shankar GM, Townsend M, Fadeeva JV, Betts V, Podlinsny MB, Cleary JP, Ashe KH, Rowan MJ, and Selkoe DJ. (2005) The role of cell-derived oligomers of Aβ in Alzheimer's disease and avenues for therapeutic intervention. Biochem Soc Trans, 33:1087-1090.
Townsend M*, Cleary JP*, Mehta T, Hofmeister J, Lesne S, O'Hare E, Walsh DM, and Selkoe DJ. (2006) Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-β oligomers. Ann of Neurology, 60:668-676.
Cleary JP, Johannsdottir R, Hofmeister J, Forster C, SantaCruz K, and Ashe KH. (2006) Cognitive and pathological effects of regulatable tau in adult mice. Alzheimer's and Dementia: The Journal of the Alzheimer's Association 2:37. (Archived abstract).
Kotilinek AL, Westerman MA, Wang Q, Panizzon K, Lim GP, Simonyi A, Lesne S, Falinska A, Younkin LH, Younkin SG, Rowan MJ, Cleary JP, Wallis RA, Sun GY, Cole G, Frautschy S, Anwyl R, and Ashe KH. (2008) Cyclooxygenase-2 inhibition improves amyloid-β-mediated suppression of memory and synaptic plasticity. Brain 131(3):651-664.
Poling A, Paisley-Morgan K, Panos JJ, Kim E-M, O'Hare E, Cleary JP, Lesne S, Ashe KH, Porritt M, and Baker LE. (2008) Oligomers of the amyloid-beta protein disrupt working memory: confirmation with two behavioral procedures. Behavioural Brain Research, 193(2):230-234.
Klyubin I, Wang O, Reed , MN, Irving EA, Upton N, Hofmeister J, Cleary JP, Anwyl R, and Rowan MJ. (2009 epub). Protection against Aβ-mediated rapid disruption of synaptic plasticity and memory by memantine. Neurobiology of Aging, 32(4):614-23 (2011).
Reed MM, Hofmeister JJ, Jungbauer L, Welzel AT, Yu C, Sherman M, Lesné S, LaDu MJ, Walsh DM, Ashe KH, Cleary JP. (2011) Cognitive effects of cell-derived and synthetically-derived Aβ oligomers. Neurobiology of Aging, 32: 1784-94.
O'Nuallain, B, Klyubin, I., McDonald, JM, Barry, A, Dykoski, RK, Cleary, JP, Martijn F.B.G. Gebbink, MF, Rowan, MJ, and Walsh, DM. (2011) A monoclonal antibody against synthetic Aβ dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aβ. J Neuro Chem, 119:189-201.
- James Cleary, PhD
- Jacki Hofmeister
- Karen Ashe (University of Minnesota, Minneapolis VA)
- Michael Lee (University of Minnesota, Minneapolis VA)
- Eugene O'Hare (Queen's University, Belfast Northern Ireland)
- Michael Rowan (Trinity College, Dublin, Ireland)
- Dominic Walsh (Harvard University, Boston MA)