P3–296: Luteinizing hormone mediates Alzheimer–type changes in neurons

Age–related increases in luteinizing hormone (LH) have recently been implicated in the etiology of Alzheimer disease (AD), particularly in mechanisms involving amyloid–beta synthesis and deposition. To further explore the potential pathophysiological mechanisms involved in the actions of LH in AD, we used an in vitro model system (primary hippocampal neurons) to examine the effects of LH on oxidative stress, cell signaling, and tau phosphorylation. Our data demonstrate that LH dose–dependently leads to increases in tau phosphorylation, ERK activation, and increases in the activity of GSK–3beta. Importantly, similar doses also lead to redox changes including increased cellular stress and reductions in cellular glutathione (GSH) levels. These results indicate that LH is likely to be pluripotent mediator of the disease since, in addition to modulating amyloid–beta–related mechanisms, LH also mediates redox and cytoskeletal imbalances associated with the modulation of endogenous antioxidant systems such as GSH as well as aberrant tau phosphorylation. Moreover, since high LH levels were associated with ERK phosphorylation and GSK–3beta, it is likely that LH may, at least partially, work via cell signaling mechanisms involving mitogenic pathways. Work in the authors' laboratories is supported by Voyager Pharmaceutical Corporation, the Alzheimer's Association, Philip Morris USA Inc. and Philip Morris International.