Behavioral phenotype and BDNF differences related to apoE isoforms and sex in young transgenic mice Ingrid Reverte a, b , Anders Bue Klein c , Cecilia Ratner c , José L. Domingo a , Maria Teresa Colomina a, b, ⁎ a Laboratory of Toxicology and Environmental Health, School of Medicine, IISPV, Universitat Rovira i Virgili, Reus, Spain b Department of Psychology and Research Center for Behavioral Assessment (CRAMC), Universitat Rovira i Virgili, Sescelades Campus, Tarragona, Spain c Neurobiology Research Unit, Copenhagen University Hospital, Righospitalet, Denmark abstract article info Article history: Received 30 April 2012 Revised 14 June 2012 Accepted 16 June 2012 Available online 24 June 2012 Keywords: Apolipoprotein E General activity Spatial learning Memory Alzheimer's disease Gender differences BDNF TrkB Human apolipoprotein E (apoE) plays an important role in lipid transport and distribution, being involved in neurite growth and neuroprotection in the brain. In humans, the apoE4 isoform is a risk factor for developing Azheimer's disease (AD), while apoE2 seems to provide neuroprotection. However, very little information is available on apoE2 genotype. In the present study, we have characterized behavioral and learning pheno- types in young transgenic mice apoE2, apoE3 and apoE4 of both sexes. We have also determined the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in cortex and hippocampus of male and female mice carrying either genotype. Our results show a worse performance of apoE4 and apoE2 mice in the acquisition of a spatial task compared to apoE3 mice, and a worse retention in apoE2 mice compared to the other two genotypes. On the other hand, an increase in the exploration of an open-field, which is com- patible with a hyperactive behavior, was found in apoE2 females, while a decreased activity was observed in apoE4 mice. Increased BDNF levels in the frontal cortex were observed in apoE2 mice compared to apoE3. These results underscore behavioral differences between apoE genotypes in young mice, as well as the exis- tence of interactions between genotype and gender, providing new valuable information on the apoE2 genotype. © 2012 Elsevier Inc. All rights reserved. Introduction In humans, apolipoprotein E (apoE) is a soluble protein involved in lipid transport and distribution (Arendt, 2001). Three allelic variants (ε2, ε3, and ε4) give rise to the major human apoE isoforms. These forms confer different risks to cardiovascular disease and metabolic syndromes through interactions with the liver X receptor (LXR) (Tao et al., 2011; Vaisi-Raygani et al., 2007). In the central ner- vous system (CNS), apoE is involved in neurogenesis, neurite growth and neuroprotection (Arendt, 2001; van Meer et al., 2007). The most common isoform in humans is apoE3, followed by apoE4 and apoE2. ApoE4 has been identified as a major genetic risk factor for developing Alzheimer's disease (AD), while the apoE2 allele has been associated with more effective neuroprotection, compared to apoE3 and apoE4. However, information on apoE2 is rather sparse (Grootendorst et al., 2005; Raber, 2008). The association of apoE4 with AD could be related to several mechanisms, such as alterations on the metabolism of beta- amyloid peptide and tau hyperphosphorylation (Raber et al., 2004), mitochondrial dysfunction, pro-inflammatory effects on microglial cells, oxidative stress and myelin alterations (Colton et al., 2005; Huang, 2006). ApoE4 is not only associated with a higher risk of developing AD, but also with a faster cognitive deterioration at the initial states of the disease, and even with memory loss in middle-aged population (Bour et al., 2008; Reitz and Mayeux, 2009). Moreover, apoE4 allele showed activity changes in prefrontal and mid-temporal cortex and in hippocampus (Dennis et al., 2010; Mondadori et al., 2007; Reiman et al., 2004). Despite the dysfunctions observed, these studies reported equivalent general cognitive performance in young apoE4 carriers comparable to non-carriers (Dennis et al., 2010; Reiman et al., 2004). In contrast, other authors reported that apoE4 children did not show recall ability in the spatial test Memory island (Acevedo et al., 2010), while young apoE4 carriers performed worse in a maze test consisting of learning a route, in comparison with apoE3 carriers (Alexander et al., 2007). There are also evidences that the apoE4 genotype affects males and females differently, being female carriers more susceptible to develop AD (Pfankuch et al., 2005). These dif- ferences between studies point to cognitive specific domain alterations related to apoE, while other capabilities remain unaltered and remark the importance of the testing procedure and the sensitivity of the test. Studies in rodents also reported apoE isoform-dependent effects on cognitive function in mice expressing apoE. ApoE4-related cogni- tive impairments in the Morris Water Maze (MWM) were more Experimental Neurology 237 (2012) 116–125 ⁎ Corresponding author at: Universitat Rovira i Virgili, Research Center for Behavior Assessment (CRAMC), Department of Psychology, Sescelades Campus, 43007 Tarragona, Spain. Fax: +34 977 558088. E-mail address: mariateresa.colomina@urv.cat (M.T. Colomina). 0014-4886/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2012.06.015 Contents lists available at SciVerse ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr