The broad, long-term goal of this application is to understand the molecular basis for cognitive impairment in Alzheimer's disease, in order to develop more effective therapies. The rationale for the experiments described below stems from our recent findings linking an aspect of cognitive decline in Tg2576 mice to the conversion of soluble to insoluble A-beta, and from our results showing improved behavioral performance following passive administration of A-beta antibodies. These observations have led us to propose that an intermediate of A-beta forming during the conversion of soluble to insoluble A-beta negatively influences cognitive function and can be neutralized with A-beta antibodies. For the sake of discussion in this application we refer to this entity as A.beta*. Using genetic and immune manipulations, we propose to test and extend the hypothesis that A.beta* causes cognitive impairment in Tg2576 and other mouse models of Alzheimer's disease. These results may provide important new information on the pathogenesis of dementia in Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065465-04
Application #
6849316
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Meinecke, Douglas L
Project Start
2002-02-01
Project End
2007-01-31
Budget Start
2005-02-14
Budget End
2006-01-31
Support Year
4
Fiscal Year
2005
Total Cost
$259,875
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Reed, Miranda N; Liu, Peng; Kotilinek, Linda A et al. (2010) Effect size of reference memory deficits in the Morris water maze in Tg2576 mice. Behav Brain Res 212:115-20
Ashe, Karen H; Zahs, Kathleen R (2010) Probing the biology of Alzheimer's disease in mice. Neuron 66:631-45
Lesne, S; Kotilinek, L; Ashe, K H (2008) Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 151:745-9
Kotilinek, Linda A; Westerman, Marcus A; Wang, Qinwen et al. (2008) Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity. Brain 131:651-64
Kotilinek, Linda A; Bacskai, Brian; Westerman, Marcus et al. (2002) Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci 22:6331-5