, 2010; Harris et al., 2003). Likewise, when full-length apoE4 was specifically expressed in neurons (NSE-apoE4 transgenic mice), these mice displayed early-onset impaired learning and memory (Buttini et al., 1999; Raber et al., 1998; Raber et al., 2000) that correlated selleck compound with multiple neuropathological effects, including

loss of synaptic connections and neurodegeneration (Buttini et al., 1999). These effects are likely mediated through apoE4 fragment generation (Brecht et al., 2004). In addition to neurodegenerative changes in the brain, the apoE4(1–272) mice display other pathologies in the hippocampus, including NFT structures rich in hyperphosphorylated tau, which were elevated by about six-fold over levels seen in nontransgenic mice (Andrews-Zwilling et al., 2010; Harris et al., 2003). Andrews-Zwilling et al. (2010) showed that apoE4 knock-in mice display

an age-dependent decrease in GABAergic interneurons selectively in the hilus of the hippocampus and that this decrease was associated with impaired learning and memory behaviors in these mice. Transgenic expression of an apoE4 truncation mutant lacking the C-terminal 27 amino acids led to an even more marked Selleck PLX-4720 decrease in GABAergic interneuron levels, along with pronounced hyperphosphorylation of tau in the hippocampus (Andrews-Zwilling Suplatast tosilate et al., 2010). Studies by Li et al. (2009) have also revealed a link between apoE4 expression and the impaired generation of new neurons, demonstrating that apoE4 knockin mice have reduced hilar GABAergic interneurons, leading to impaired hippocampal neurogenesis. Based on these data, it has been postulated

that the parallel decreases in interneuron levels and hippocampal neurogenesis are responsible for the behavioral impairments seen in apoE4 transgenic mice (Andrews-Zwilling et al., 2010; Huang and Mucke, 2012; Li et al., 2009). In support of this hypothesis, optogenetic manipulations of hilar GABAergic interneurons confirmed that functional inhibition of this specific neuronal population results in spatial learning and memory deficits, as seen in apoE4 knockin mice (Andrews-Zwilling et al., 2012). These effects on hippocampal GABAergic neurons and memory behaviors are consistent across studies, but nonetheless reveal interesting differences depending on whether apoE4 is expressed selectively in neurons versus ubiquitously in the brain. For example, apoE4 knockin mice showed impaired learning and memory behaviors, but at a later time point (16 months of age) compared with neuron-specific (i.e., Thy1.2- or NSE-promoter-driven) apoE4 mice (Andrews-Zwilling et al., 2010).