Transgenic mouse models offer great promise for both defining the pathological mechanisms of Alzheimer's Disease (AD) and assisting in the development of effective therapies. The Tg2576 line of transgenic mice (Hsiao et al., 1996) demonstrates an important number of pathological features that reveal a striking correspondence to human AD, including the region-specific, age-dependent elevation of Abeta levels (both the 1-40 and 1-42/43 isoforms) and development of dense-core amyloid plaques. Perhaps most importantly, the Tg2576 mice also showed deficits in performance on learning and memory tasks, at the same age at which they demonstrated explosive increases in neuropathological symptoms. Moreover, our preliminary data indicate that the behavioral deficits were correlated with the development of abnormalities in long-term synaptic plasticity. We propose to extend our knowledge of the behavioral and physiological phenotype of the Tg2576 mouse. We have developed a focused set of behavioral tests. These behavioral tests will also allow us to test mice frequently and at regular intervals, so that we will develop a better understanding of not only the nature of the behavioral phenotype, but also the time-course of its development. At the same time, we will examine in detail the synaptic physiology of the Tg2576 mice, both in vitro and in vivo. As we learn more about the behavioral and physiological phenotype, including the developmental time-course of each, we ill be in a better position to document and understand the correlation between synaptic physiology, behavior, and neuropathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG015453-01A1
Application #
6200525
Study Section
Project Start
1999-06-15
Project End
2000-04-30
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Ashe, Karen H; Zahs, Kathleen R (2010) Probing the biology of Alzheimer's disease in mice. Neuron 66:631-45
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
Jankowsky, Joanna L; Melnikova, Tatiana; Fadale, Daniel J et al. (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease. J Neurosci 25:5217-24
Jankowsky, Joanna L; Slunt, Hilda H; Gonzales, Victoria et al. (2005) Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med 2:e355
Park, Laibaik; Anrather, Josef; Zhou, Ping et al. (2005) NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25:1769-77
Santacruz, K; Lewis, J; Spires, T et al. (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476-81
Fukumoto, Hiroaki; Rosene, Douglas L; Moss, Mark B et al. (2004) Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am J Pathol 164:719-25
Kawarabayashi, Takeshi; Shoji, Mikio; Younkin, Linda H et al. (2004) Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. J Neurosci 24:3801-9
Krezowski, Joseph; Knudson, Danielle; Ebeling, Christine et al. (2004) Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression. Hum Mol Genet 13:1989-97
Bacskai, Brian J; Hickey, Gregory A; Skoch, Jesse et al. (2003) Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A 100:12462-7

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