YEARS

1999-2004

AUTHORS

Karen H Ashe

TITLE

BIOLOGY OF ALZHEIMERS DISEASE IN TRANSGENIC MICE

ABSTRACT

The central aim of this proposal is to understand the biological effects of Alzheimer amyloid precursor protein (APP) expression in transgenic (Tg) mice, which we believe will in turn reflect important aspects of the biology of Alzheimer's disease (AD), whose fundamental etiology is unknown. To accomplish this we propose to build upon our knowledge of Tg mice, designated Tg(HuAPP695.K670N/M671L)2576 (or Tg2576), expressing the 695 amino-acid isoform of APP with mutations at amino acids 670 and 671 (APP-77O numbering) found in a large Swedish family with Alzheimer's disease. These mice have age-related deficits in learning and memory associated with the appearance of classic senile plaques. They shall enable us to extend our understanding of the pathophysiology and neurobiology of AD using genetic (Drs. George Carlson and Karen Hsiao, Projects 2 and 1), anatomical and molecular pathological (Dr. Brad Hyman, Project 3), and physiological and behavioral methods (Dr. Paul Chapman, Project 4). By comparing these mice with transgenic mice expressing equivalent levels of wild-type APP-695 (Dr. Steven Younkin, Core B) we shall be able to ascertain which behavioral, neurophysiological and neuropathological abnormalities are related to an overall increase in brain APP expression and which are due to APP cleavage products, including Abeta (Dr. Steven Younkin, Core B). Moreover, we shall attempt to determine the form (soluble or insoluble) and location (intracellular or extracellular) of A beta that best corresponds to specific phenotypic traits. Modifications of the transgene used in Tg2576 mice may also allow us to understand the role of aging in triggering the deficits we observe and delineate temporal windows during which deficits can be reversed (Dr. Karen Hsiao, Project 1). If the basic biological mechanisms for the age-related cognitive deficits in AD are discovered, more effective drugs than are currently available may be designed to circumvent them.

FUNDED PUBLICATIONS

  • Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.
  • Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer's disease.
  • Probing the biology of Alzheimer's disease in mice.
  • 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.
  • Learning and memory in transgenic mice modeling Alzheimer's disease.
  • Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption.
  • Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice.
  • In vivo multiphoton imaging of a transgenic mouse model of Alzheimer disease reveals marked thioflavine-S-associated alterations in neurite trajectories.
  • Imaging of amyloid-beta deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy.
  • Tau suppression in a neurodegenerative mouse model improves memory function.
  • Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity.
  • NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide.
  • Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease.
  • Beta-secretase activity increases with aging in human, monkey, and mouse brain.
  • Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy
  • Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression.
  • Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy.
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    36 TRIPLES      17 PREDICATES      37 URIs      9 LITERALS

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