| First Author | Fowler SW | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 23 | Pages | 7871-85 |
| PubMed ID | 24899710 | Mgi Jnum | J:244396 |
| Mgi Id | MGI:5913175 | Doi | 10.1523/JNEUROSCI.0572-14.2014 |
| Citation | Fowler SW, et al. (2014) Genetic modulation of soluble Abeta rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease. J Neurosci 34(23):7871-85 |
| abstractText | 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-beta (Abeta) 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 Abeta 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 Abeta from that of deposited amyloid on cognitive function and synaptic structure. Rapid inhibition of transgenic APP modulated the production of Abeta 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 Abeta with a gamma-secretase inhibitor provided similar improvement, suggesting that transgene suppression restored cognition, at least in part by lowering Abeta. Cognitive improvement coincided with reduced levels of synaptotoxic Abeta oligomers, greater synaptic density surrounding amyloid plaques, and increased expression of presynaptic and postsynaptic markers. Together these findings indicate that transient Abeta 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. |
