title: Genetic modulation of soluble Aβ rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease.
abstract: 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.
authors.affiliation: Departments of Neuroscience and.
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Fowler
authors.affiliation: Departments of Neuroscience and.
authors.forename: Angie C A
authors.initials: AC
authors.lastname: Chiang
authors.affiliation: Departments of Neuroscience and Texas A&M Health Science Center, College Station, Texas 77843.
authors.forename: Ricky R
authors.initials: RR
authors.lastname: Savjani
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55454, and.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Larson
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55454, and.
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Sherman
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Dorothy R
authors.initials: DR
authors.lastname: Schuler
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.affiliation: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55454, and.
authors.forename: Sylvain E
authors.initials: SE
authors.lastname: Lesné
authors.affiliation: Departments of Neuroscience and Neurology and Neurosurgery, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, jankowsk@bcm.edu.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Jankowsky
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001381:Azepines / Q000008:administration & dosage; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D058225:Plaque, Amyloid / Q000139:chemically induced / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D001381:Azepines; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D053829:Amyloid Precursor Protein Secretases; D004318:Doxycycline; D000409:Alanine
keywords: APP; TTA; amyloid; amyloid precursor protein; oligomer; tetracycline transactivator