title: Reversal of learning deficits in hAPP transgenic mice carrying a mutation at Asp664: a role for early experience.
abstract: In addition to the cleavages that generate amyloid-beta (Abeta), the Abeta-precursor protein (APP) is processed at Asp664, releasing a second toxic peptide (APP-C31). Transgenic mice otherwise identical to a well-characterized model of AD, PDAPP mice, but carrying a mutation that obliterates Asp664 show a reversal of AD-like deficits in memory and in non-cognitive components of behaviour in spite of accumulating high levels of Abeta. These results suggest that cleavage of APP at Asp664 plays a role in the generation of AD-like deficits, and that a major pathway of Abeta toxicity in vivo, or a pathway that crucially impinges on it, may depend on cleavage of APP at Asp664. Since young PDAPP(D664A) mice showed an akinetic phenotype when first required to swim, we trained a 3-month-old (mo) cohort to criterion (normal swimming), and briefly exposed it to the Morris water maze (MWM) environment prior to training at 7 mo, to avoid potentially confounding effects of the akinetic phenotype in MWM studies. Prior experience decreased floating in PDAPP(D664A) mice but not in PDAPP nor in non-Tg groups. While learning was restored in experienced PDAPP(D664A) mice, it was indistinguishable from both non-Tg as well as from PDAPP mice in naïve PDAPP(D664A) animals. Floating did not correlate with worse performance in naïve PDAPP(D664A) mice, suggesting that the contribution of prior experience to improved performance is related to its cognitive effects but not to non-cognitive components of behaviour. Our results suggest that early experience reduces the contribution of non-cognitive components of behaviour to performance, and may contribute to the restoration of learning at later ages in PDAPP(D664A) mice.
authors.affiliation: Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, United States.
authors.forename: Junli
authors.initials: J
authors.lastname: Zhang
authors.forename: Olivia F
authors.initials: OF
authors.lastname: Gorostiza
authors.forename: Huidong
authors.initials: H
authors.lastname: Tang
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: Veronica
authors.initials: V
authors.lastname: Galvan
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D007858:Learning / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation / Q000235:genetics*; D013037:Spatial Behavior / Q000502:physiology; D013550:Swimming
chemical_list: D016564:Amyloid beta-Protein Precursor