REELIN SIGNAL TRANSDUCTION PATHWAY IN APOE3 AND APOE4 TRANSGENIC MICE

Purpose: The ɛ4 allele of apolipoprotein E (APOE) has been associated with increased risk for the development of late-onset, familial and sporadic Alzheimer's disease (AD). The mechanisms underlying the increase risk of AD development conferred by the ɛ4 allele remains unclear. Reelin and its associated signal transduction pathway are involved in developmental processes, and more specifically, in regulating neuronal migration and cortical lamination in the embryotic brain. Recently, it has been determined that reelin is present in the adult brain throughout the neocortex and hippocampus suggesting a potential role in synaptic plasticity. Furthermore, studies have shown that disruption of the reelin pathway led to decreased memory, impaired long-term potentiation (LTP), and affected dendritic spine morphology. This preliminary study investigated the role of the reelin pathway as a potential mechanism underlying the functional declines associated with APOE polymorphism. Methods: Separate groups of young (7 months) male and female mice expressing human apolipoprotein E4 or E3 in glial cells) were subjected to a series of behavioral tests to measure spontaneous activity, reflexes (walking initiation, alley turn, and negative geotaxis), motor function (wire suspension, bridge walking, coordinated running), and cognitive function (spatial water maze, active avoidance). Brain regions were dissected to determine the levels of reelin and other contributors of its pathway such as dab1, fyn, AMPA and NR2A via western blot analyses. Results: ApoE3 mice took longer latencies to fall in bridge walking, wire suspension, and coordinated running tasks than their ApoE4 counterparts, most notably in males. In the active avoidance task, ApoE3 female mice took fewer trials to reach criterion in session 3 over their ApoE4 counterparts. Western blot analyses will reveal whether reelin may underlie the differences in brain function between genotype and sex. Conclusions: Our results indicate that there may be functional differences between sex as well as ApoE polymorphism. Western blot analyses will reveal whether reelin, dab1, fyn, AMPA and NR2A may underlie the differences in brain function between genotype and sex.