title: Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer-amyloidosis.
abstract: Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet-Off vector systems provide an alternative model for assessing short- and long-term effects of Aβ-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aβ has been suppressed. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aβ production produced highly significant improvements in performing short-term spatial memory tasks, which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Aβ production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aβ42. Additionally, we observed persistent levels of Aβ-immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Aβ assemblies and low, but detectable solubilizable Aβ42 peptides. These findings implicate complex relationships between accumulating Aβ and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis.
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Tatiana
authors: T
authors: Melnikova
authors: Susan
authors: S
authors: Fromholt
authors: HyunSu
authors: H
authors: Kim
authors: Deidre
authors: D
authors: Lee
authors: Guilian
authors: G
authors: Xu
authors: Ashleigh
authors: A
authors: Price
authors: Brenda D
authors: BD
authors: Moore
authors: Todd E
authors: TE
authors: Golde
authors: Kevin M
authors: KM
authors: Felsenstein
authors: Alena
authors: A
authors: Savonenko
authors: David R
authors: DR
authors: Borchelt
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000150:complications* / Q000178:diet therapy / Q000235:genetics / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D003072:Cognition Disorders / Q000178:diet therapy / Q000209:etiology* / Q000473:pathology; D004192:Discrimination, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D058225:Plaque, Amyloid / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects; D013028:Space Perception; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004318:Doxycycline