Elevations of luteinizing hormone (LH) levels with aging have been implicated in the development of Alzheimer's Disease (AD); evidence from clinical studies suggests that treatment of patients with a GnRH antagonist, Lupron, reduces LH levels, slows the progression of AD and improves cognitive function. Although there have been studies implicating LH effects on processing of amyloid-? in the murine brain and M17 cells, there is surprisingly little known about direct effects of LH on the nervous system. Recent studies addressing this question have used fixed concentrations of LH and ignored the fact that LH secretion, particular in women, is strongly pulsatile and that there are effects of aging on the amplitude of LH pulses. Here we propose to examine the effects of high amplitude LH pulses on M17 cells, a neuroblastoma cell line which expresses LH receptors and processes amyloid-? from its precursor. LH receptor pulses characteristic of young women and of post-menopausal women will be compared. We hypothesize that exposure of M17 neuroblastoma cells to LH pulses at amplitudes characteristic of those in post-menopausal women significantly increases the secretion of amyloid-?, a protein that appears in excess in the brains of patients with AD. These studies will also develop, for the first time, strategies for imaging events associated with LH-mediated signaling in living cells during exposure to hormone. We have chosen the R03 mechanism for this application for several reasons. This project involves the """"""""development of new research technology"""""""", a goal of the NICHD's R03 funding mechanism. Support for this R03 application will permit a proof-of-principal demonstration of several biophysical approaches to monitor LH receptor function in real time. These approaches will be incorporated into an R01 application containing a detailed examination of signaling by ovarian cells in response to pre-ovulatory LH pulses and the LH surge. In addition, this project is of limited scope and likely to be completed within two years. Shared support for this project from the Biology of Aging Program (BAP) in the National Institute of Aging might also be appropriate. Changes in LH pulsatility with aging are implicated in the development of AD and thus represent an """"""""adverse change"""""""" that may be a risk factor for development of a disease that occurs with high frequency in an aging population. ? ? ?
| Wolf-Ringwall, Amber L; Winter, Peter W; Roess, Deborah A et al. (2014) Luteinizing hormone receptors are confined in mesoscale plasma membrane microdomains throughout recovery from receptor desensitization. Cell Biochem Biophys 68:561-9 |
