Estrogen, aging, and LTP in apoE replacement mice

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The administration of estrogen to improve cognition in aging women is controversial because of uncertainty about whether its benefits outweigh other health risks. The presence of the APOE epsilon 4 (apoE4) allele is increasingly recognized as an independent risk factor for age-related cognitive decline. Several lines of evidence suggest an estrogen-apoE interaction that may be isoform specific. Within the scope of this pilot project we will examine the presence of the apoE epsilon4 allele, age at estrogen administration, and tempo of estrogen administration as three potential mitigating factors in the efficacy of estrogen therapy. To address these aims we will use the electrophysiologic paradigm of long-term potentiation (LTP), measured in dentate gyrus, as an in vitro model of memory formation and neural repair. We will compare the effects of both subacute and chronic estrogen delivery on LTP using hippocampal slices prepared from young adult and middle-aged ovariectomized (OVX) human targeted replacement apoE3 and apoE4 mice. This project will provide novel information about interactions among apoE isoform and estrogen, and will complement ongoing investigations of the effects of amyloid-beta and apoE isoform on synaptic plasticity. Together these studies will help define a hierarchy among risk factors for impaired synaptic plasticity in vitro and will lead to future studies of the underlying cellular mechanisms (i.e., via patch clamp experiments). They will also serve as a complement to future behavioral studies in the elucidation of vulnerability to age-related memory loss, including that related to Alzheimer disease, with the ultimate goal of neuroplasticity rescue and the slowing or prevention of cognitive decline.