RT Journal Article
SR Electronic
T1 Genetic Modulation of Soluble Aβ Rescues Cognitive and Synaptic Impairment in a Mouse Model of Alzheimer's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7871
OP 7885
DO 10.1523/JNEUROSCI.0572-14.2014
VO 34
IS 23
A1 Stephanie W. Fowler
A1 Angie C. A. Chiang
A1 Ricky R. Savjani
A1 Megan E. Larson
A1 Mathew A. Sherman
A1 Dorothy R. Schuler
A1 John R. Cirrito
A1 Sylvain E. Lesné
A1 Joanna L. Jankowsky
YR 2014
UL http://www.jneurosci.org/content/34/23/7871.abstract
AB An unresolved 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-β (Aβ) 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 Aβ 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 Aβ from that of deposited amyloid on cognitive function and synaptic structure. Rapid inhibition of transgenic APP modulated the production of Aβ without affecting pre-existing 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 Aβ with a γ-secretase inhibitor provided similar improvement, suggesting that transgene suppression restored cognition, at least in part by lowering Aβ. Cognitive improvement coincided with reduced levels of synaptotoxic Aβ oligomers, greater synaptic density surrounding amyloid plaques, and increased expression of presynaptic and postsynaptic markers. Together these findings indicate that transient Aβ 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.