In some cases, memory impairment appears after amyloid burden reaches moderate to severe levels ( Savonenko et al., 2005 Eriksen and Janus, 2007) and others report memory dysfunction before amyloid deposition occurs or reaches moderate levels ( Hsiao et al., 1996 Dodart et al., 1999 Moechars et al., 1999 Chen et al., 2000 Janus et al., 2000 Westerman et al., 2002). No consensus has emerged regarding the basis for memory dysfunction in mice that model Alzheimer amyloidosis. Transgenic mice that express mutant APP, or mutant APP with mutant PS1, develop Alzheimer-type amyloidosis and memory dysfunction (for review, see Jankowsky et al., 2002 Eriksen and Janus, 2007). Early-onset familial AD is also associated with mutations in two functionally related proteins termed presenilin 1 and 2 ( Rogaev et al., 1995), which are interchangeable components of γ-secretase, the multiprotein complex that catalyzes one of the critical proteolytic events that produces Aβ42 (for review, see Li et al., 2009). This longer Aβ peptide is most prone to produce amyloid deposits ( Iwatsubo et al., 1994 McGowan et al., 2005).
Disease-causing mutations in the amyloid precursor protein (APP), which produces the Aβ peptide through a series of proteolytic events (for review, see Lichtenthaler et al., 2011), generally lead to enhanced levels of Aβ42 peptides ( Citron et al., 1992, 1997 Suzuki et al., 1994 Scheuner et al., 1996 Kwok et al., 2000 De Jonghe et al., 2001 Bentahir et al., 2006 Di et al., 2009 Zhou et al., 2011). Multiple lines of genetic evidence link the accumulation and/or deposition of amyloid β peptide (Aβ) as a causative factor in Alzheimer's disease (AD) (for review, see Selkoe and Podlisny, 2002). 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. 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. Additionally, we observed persistent levels of Aβ-immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. As expected, amyloid deposits persisted after new APP/Aβ production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aβ42. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. 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. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. 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. 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.