Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 23, Pages 7871-7885Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0572-14.2014
Keywords
amyloid; amyloid precursor protein; APP; oligomer; tetracycline transactivator; TTA
Categories
Funding
- National Institutes of Health Office of the Director New Innovator [DP2 OD001734]
- Robert A. and Rene E. Belfer Family Foundation
- National Institute of Aging Biology of Aging training [T32 AG000183]
- Gates Millennium Scholarship
- National Institute of Health [R00-AG031293, R01-NS033249]
- startup funds from the University of Minnesota Medical Foundation
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Anunresolved debate in Alzheimer's disease (AD) is whether amyloid plaques are pathogenic, causing overt physical disruption of neural circuits, or protective, sequestering soluble forms of amyloid-beta (A beta) that initiate synaptic damage and cognitive decline. Few animal models of AD have been capable of isolating the relative contribution made by soluble and insoluble forms of A beta to the behavioral symptoms and biochemical consequences of the disease. Here we use a controllable transgenic mouse model expressing a mutant form of amyloid precursor protein (APP) to distinguish the impact of soluble A beta from that of deposited amyloid on cognitive function and synaptic structure. Rapid inhibition of transgenic APP modulated the production of A beta without affecting preexisting amyloid deposits and restored cognitive performance to the level of healthy controls in Morris water maze, radial arm water maze, and fear conditioning. Selective reduction of A beta with a secretase inhibitor provided similar improvement, suggesting that transgene suppression restored cognition, at least in part by lowering A beta. Cognitive improvement coincided with reduced levels of synaptotoxic A beta oligomers, greater synaptic density surrounding amyloid plaques, and increased expression of presynaptic and postsynaptic markers. Together these findings indicate that transient A beta species underlie much of the cognitive and synaptic deficits observed in this model and demonstrate that significant functional and structural recovery can be attained without removing deposited amyloid.
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