Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: Relationships to β-amyloid deposition and neurotransmitter abnormalities
Introduction
Alzheimer's disease (AD) dementia is characterized neuropathologically by deposits of β-amyloid peptides (Aβ), neurofibrillary tangles, reactive astrocytosis, activation of microglial cells, and deficits in the cholinergic system (Terry and Katzman, 1983, Whitehouse et al., 1981). Studies of familial AD have strongly implicated increased production of Aβ42 as one initiator of the disease; however, relating Aβ42 production/deposition and cognitive impairment in human AD has not consistently established linkage (Braak and Braak, 1990, Braak and Braak, 1996, Braak et al., 1993, Braak et al., 1996). Whether Aβ peptides, in any physical state, are sufficient to diminish cognitive function has been extensively studied in transgenic mice that model AD-like amyloid deposition by expressing mutant amyloid precursor protein (APP), with and without mutant presenilin 1 (PS1) (for reviews, see Ashe, 2001, Chapman et al., 2001). Some of these studies have reported data consistent with the idea that nonfibrillar Aβ may induce cognitive deficits (Dodart et al., 1999, Hsia et al., 1999, Moechars et al., 1999, Raber et al., 2000), whereas other studies report cognitive deficits only after a significant accumulation of fibrillar Aβ (Arendash et al., 2001, Puolivali et al., 2002). A confounding factor in interpreting these different outcomes in mice is that the level of mutant APP expression, and the promoter used to drive the transgene, varies substantially; and in some cases it has been difficult to differentiate the effects of APP holoprotein from the effects of Aβ due to age-independent behavioral changes. Notably, pathological outcomes in mice that express full-length mutant APP (with or without mutant PS1) are relatively uniform. If there is sufficient expression of APP, there will be age-dependent accumulation of amyloid plaques with increased gliosis and alterations in microglia (for review, see Jankowsky et al., 2002). One goal therefore in characterizing the cognitive behavior of these different models is to try and establish which phenotypes may be model-dependent as opposed to model-independent. In this context, no single model provides an all-encompassing view of the biology behind this disease; rather, a consensus builds from identifying the most common and reproducible features from different models.
In the present study, we focus on the cognitive behavior of mice expressing APPswe (Line C3-3) at levels that do not inherently disturb ability to perform cognitive tasks out to 24 months of age (Savonenko et al., 2003). To specifically augment the amyloidogenic processing of APPswe, and the deposition of amyloid, we crossed these mice to animals expressing PS1dE9. Mice expressing APPswe alone (Line C3-3) do not develop visible amyloid deposits until after 24 months of age whereas co-expression of PS1dE9 specifically elevates Aβ42 levels and induces amyloid deposition by 6 months of age (Jankowsky et al., 2004, Lesuisse et al., 2001). Hence, this model allows for the dissection of the impact of mutant APP holoprotein, nonfibrillar Aβ40 and 42, and fibrillar amyloid deposits on the cognitive function of mice. The cognitive abilities of mice co-expressing APPswe/PS1dE9 were compared to mice expressing each transgene alone and to nontransgenic littermates. We analyzed multiple memory systems concordantly, because it is well known that cognitive deficits in Alzheimer's disease patients involve multiple cognitive domains that decline at independent rates (Ober and Shenaut, 1999, Perry and Hodges, 2000, Welsh et al., 1991). Mice were studied in an ordered series of water maze tasks that started with a classic version of the Morris Water Maze, which requires incremental learning of a constant platform location over multiple days of training, and results in formation of long-lasting reference memory (for review, see Squire, 1994). This task was followed by Repeated Reversal and Radial Water Maze tasks, where the platform location was changed daily. All tasks were conducted in the same spatial environment such that learning new platform locations greatly relied on successful suppression of old memory traces. In this setting, the type of memory measured in the Repeated Reversals and Radial Water Maze tasks was akin to episodic memory (Tulving, 1983). It requires rapid formation of memory traces of unique events in time (daily new platform location) and the ability to distinguish those events from other related events (suppression of memories for old platform locations). To relate changes in cognitive performance (in all tasks) to pathologic and neurochemical events, we utilized factor analysis.
Our data indicate that, in the lines of APPswe and PS1dE9 mice that we have studied here, increases in amyloid burden that occur between 6 and 18 months of age in APPswe/PS1dE9 mice correlate highly with deficits in episodic-like memory. These changes in cognitive performance were accompanied by only mild diminutions in cholinergic markers (acetylcholinesterase and acetylcholine transferase) and somatostatin (SRIF) levels. Overall, our data indicate that, independently of whether major losses in cholinergic function occur, some form of Aβ associated with amyloid deposition moderately impacts spatial reference memory while dramatically interfering with cognitive systems responsible for episodic-like memory.
Section snippets
Subjects
Male APPswe, PS1dE9, and APPswe/PS1dE9 transgenic mice and nontransgenic littermate controls (NTg) were used in this study (n = 68). Mice were derived from previously described lines of transgenic mice (Borchelt et al., 1996, Lee et al., 1997, Lesuisse et al., 2001). APPswe transgenic mice (line C3-3) express a chimeric mouse/human (Mo/Hu) APP-695 with mutations linked to familial AD (KM 593/594 NL) (Borchelt et al., 1996). The C3-3 line has been backcrossed to C57BL/6J mice for 10 generations
Place discrimination in water maze (spatial reference memory)
Spatial reference memory was analyzed in the Morris Water Maze with a constant platform position across 4 days of training. Platform trials, in which the platform was hidden but accessible for the mouse, were run in blocks of 10 trials per day. Probe trials, in which the platform was lowered for a variable interval, were conducted at the beginning and the end of daily training.
Discussion
The present study clearly demonstrates that in mice co-expressing APPswe and PS1dE9 transgenes memory declines as a function of age. By using factor and correlation analyses, we show that total Aβ loads in the brains of these transgenic mice significantly correlate with deficits in episodic-like memory. Cognitive impairment also coincided with mild reductions in the activities of cholinergic markers in the hippocampus and cortex and somatostatin levels in the cortex. These data suggest that
Conclusions
In summary, we demonstrate that the congenic APPswe/PS1dE9 mice studied here develop age-related deficits that may not be a “one-time” event (an “onset” approach) but rather are characterized as a multistage process where different memory systems decline at different rates. Multivariable statistical and behavioral analyses indicated that reference and episodic-like memories in our APPswe/PS1dE9 mice have different sensitivities to increasing Aβ loads. Episodic-like memory is the most sensitive
Acknowledgments
This study was supported by the National Institute on Aging (Alzheimer's Disease Research Center AG05146). The authors would like to thank Allegra Heinrichs, Julia Hsiao, Jack Tseng, Jane Kim, Lawrence Huang, Kelly Straub, and Seung-Hyun Woo for their assistance with behavioral testing and data entry.
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