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 Aß-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsitTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aß has been suppressed. We find that 12- to 13-month-old APPsitTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aß 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/Aß production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aß42. Additionally, we observed persistent levels of Aß-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 Aß assemblies and low, but detectable solubilizable Aß42 peptides. These findings implicate complex relationships between accumulating Aß and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis.