BEHAVIORAL NEUROSCIENCE Genetic reductions of b-site amyloid precursor protein- cleaving enzyme 1 and amyloid-b ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer’s disease model mice Latha Devi and Masuo Ohno Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA Keywords: b-secretase, APP transgenic, BACE1, implicit memory, knockout Abstract Although transgenic mouse models of Alzheimer’s disease (AD) recapitulate amyloid-b (Ab)-related pathologies and cognitive impairments, previous studies have mainly evaluated their hippocampus-dependent memory dysfunctions using behavioral tasks such as the water maze and fear conditioning. However, multiple memory systems become impaired in AD as the disease progresses and it is important to test whether other forms of memory are affected in AD models. This study was designed to use conditioned taste aversion (CTA) and contextual fear conditioning paradigms to compare the phenotypes of hippocampus- independent and -dependent memory functions, respectively, in 5XFAD amyloid precursor protein ⁄ presenilin-1 transgenic mice that harbor five familial AD mutations. Although both types of memory were significantly impaired in 5XFAD mice, the onset of CTA memory deficits (9 months of age) was delayed compared with that of contextual memory deficits (6 months of age). Furthermore, 5XFAD mice that were genetically engineered to have reduced levels of b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) (BACE1 + ⁄ ) Æ5XFAD) exhibited improved CTA memory, which was equivalent to the performance of wild- type controls. Importantly, elevated levels of cerebral b-secretase-cleaved C-terminal fragment (C99) and Ab peptides in 5XFAD mice were significantly reduced in BACE1 + ⁄ ) Æ5XFAD mice. Furthermore, Ab deposition in the insular cortex and basolateral amygdala, two brain regions that are critically involved in CTA performance, was also reduced in BACE1 + ⁄ ) Æ5XFAD compared with 5XFAD mice. Our findings indicate that the CTA paradigm is useful for evaluating a hippocampus-independent form of memory defect in AD model mice, which is sensitive to rescue by partial reductions of the b-secretase BACE1 and consequently of cerebral Ab. Introduction Animal models of Alzheimer’s disease (AD) have dramatically increased our understanding of the molecular and pathophysiological mechanisms of this intractable disease (LaFerla & Oddo, 2005; McGowan et al., 2006; Eriksen & Janus, 2007; Gotz & Ittner, 2008). In particular, extensive studies have tested AD-related cognitive impairments in transgenic mice that overexpress mutant forms of human amyloid precursor protein (APP) using a battery of memory assays including the Morris water maze, Y-maze, fear conditioning and object or social recognition (Ashe, 2001; Kobayashi & Chen, 2005; Eriksen & Janus, 2007). These behavioral investigations have successfully characterized progressive and amyloid-b (Ab)-dependent deficits in the hippocampus-dependent memory function in APP mice. Meanwhile, two major memory systems are distinguished: explicit memory refers to a conscious recollection of specific facts and events under the control of the hippocampus and related temporal lobe connections, whereas implicit memory refers to an unconscious acquisition of information and is independent of hippocampal function (Squire, 1992). Although not only explicit but also implicit memory is affected as a consequence of AD neuropathology (Carlesimo & Oscar- Berman, 1992; Jelicic et al., 1995; Meiran & Jelicic, 1995; Fleisch- man et al., 2005), little is known about the implicit memory phenotypes in APP transgenic mice as opposed to their well- documented explicit memory deficits. Conditioned taste aversion (CTA) is a simple associative memory task, in which animals learn to avoid a novel taste such as saccharin solution [conditioned stimulus (CS)] that is paired with an aversive unconditioned stimulus (US) such as malaise-inducing agents (Welzl et al., 2001; Bermudez-Rattoni, 2004). Although CTA memory formation involves cortical areas including the insular cortex and subcortical regions such as the amygdala, lesions of the hippocampus exert little or no effect on CTA performance (Yamamoto & Fujimoto, 1991; Welzl et al., 2001; Bermudez-Rattoni, 2004; Josselyn et al., 2004; Ding et al., 2008). In this study, we applied a hippocampus- Correspondence: Dr Masuo Ohno, as above. E-mail: mohno@nki.rfmh.org Received 3 August 2009, revised 15 October 2009, accepted 19 October 2009 European Journal of Neuroscience, Vol. 31, pp. 110–118, 2010 doi:10.1111/j.1460-9568.2009.07031.x ª The Authors (2009). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience