Isoform‐specific effects of apolipoprotein E on cognitive performance in targeted‐replacement mice overexpressing human APP

Abstract

The ε4 allele of apolipoprotein E (apoE4) is the predominant genetic risk factor for late-onset Alzheimer's disease (AD) and is also implicated in cognitive deficits associated with normal aging. The biological mechanisms by which APOE genotype affects cognitive processes or AD pathogenesis remain unclear, but interactions of apoE with amyloid β peptide (Aβ) are thought to play an important role in mediating apoE's isoformspecific effects on brain function. Here, we investigated the potential isoform-dependent effects of apoE on behavioral and cognitive performance in human apoE3 and apoE4 targeted-replacement (TR) mice that also overexpress the human amyloid precursor protein (APP). Beginning at 6-7 months of age, female APP-Yac/apoE3-TR ('apoE3') and APP-Yac/apoE4-TR ('apoE4') mice were tested on a battery of tests to evaluate basic sensorimotor functioning, spatial working memory, spatial recognition, episodic-like memory and attentional processing. Compared with apoE3 mice, a generalized reduction in locomotor activity was observed in apoE4 mice. Moderate, but significant, cognitive impairments were also detected in apoE4 mice in the novel object-location preference task, the contextual fear conditioning test, and a two-choice visual discrimination/detection test, however spontaneous alternation performance in the Y-maze was spared. These results offer additional support for the negative impact of apoE4 on both memory and attention and further suggest that APP-Yac/apoE-TR mice provide a novel and useful model for investigating the role of apoE in mediating susceptibility to cognitive decline.

Hippocampus-Related Cognitive Impairments in Young apoE4 Targeted Replacement Mice

“…The study revealed that the performance of the apoE4 mice in the object recognition and Morris water maze was impaired relative to that of the apoE3 mice and that it was also impaired in the contextual but not in the cued fear conditioning response.These findings are in accordance with previous results obtained utilizing a dry version of the Morris water maze and fear conditioning test results, which were obtained using young apoE4 mice [23,30]. They also extend previous studies that revealed that adult apoE4 mice are cognitively impaired [32,34,36,37,41,42,43,44] and suggest that, like in humans, the apoE4-driven cognitive impairments begin early in life [45,46]. …”

“…On day 3, the mice were placed in the original conditioning chamber (context A) and kept there for 300 s without either the tone or the foot shock. The freezing behavior of the mice, which is an indication of fear memory, was recorded and analyzed utilizing the FreezFrame 3.0 video tracking software system and the FreezView software system [29,31,32,33]. …”

ApoE4 confers better spatial memory than apoE3 in young adult hAPP-Yac/apoE-TR mice

“…Both groups showed similar velocities throughout testing and performed similarly well in the visible-platform task, suggesting that differences in hidden-platform performance were not related to differences in sensory-motor abilities or other confounding factors like motivation. Similarly to what was found in older hAPP-Yac/apoE female mice [19] in different settings, hAPP-Yac/apoE4-TR male mice were slightly less active than hAPP-Yac/apoE3-TR mice during the first hour spent in a new environment and during the 21 h session after habituation to the activity device. Interestingly, hAPP-Yac/apoE4-TR mice were also less active during the free swim habituation trial, but not during subsequent water-maze training.…”

“…Since human APP and apoE genes differ from their respective homologues in mice, these bigenic mice provide an interesting tool to study specific in vivo interactions between human apoE isoforms and APP at the behavioral level. Interestingly, spatial memory performances are preserved in 4.5-9 months old single transgenic hAPP-YAC mice [20], whereas the bigenic hAPP-Yac/apoE4-TR female mice, but not males, showed some early deficits in spatial memory, fear conditioning and attentional tasks compared to hAPP/apoE3-TR mice at the age of 6-7 months [19,21]. The cognitive status of younger hAPP-Yac/apoE-TR mice is still unknown.…”

“…Thus, APP may be involved, at least partly, in the effects of apoE on cognition. The hAPP-Yac/apoE-TR bigenic mouse lines were recently generated by crossing apoE-TR mice with hAPP-YAC mice [19]. They express human apoE isoforms at physiological levels and normal human APP in addition to murine APP.…”