TY - JOUR T1 - Ovarian cycle stages modulate Alzheimer-related cognitive and brain network alterations in female mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0132-17.2018 SP - ENEURO.0132-17.2018 AU - Lauren Broestl AU - Kurtresha Worden AU - Arturo J. Moreno AU - Emily J. Davis AU - Dan Wang AU - Bayardo Garay AU - Tanya Singh AU - Laure Verret AU - Jorge J. Palop AU - Dena B. Dubal Y1 - 2018/12/03 UR - http://www.eneuro.org/content/early/2018/12/03/ENEURO.0132-17.2018.abstract N2 - Alzheimer’s disease (AD) begins several decades before the onset of clinical symptoms, at a time when women may still undergo reproductive cycling. Whether ovarian functions alter substrates of AD pathogenesis is unknown. Here we show that ovarian cycles stages significantly modulate AD-related alterations in neural network patterns, cognitive impairments, and pathogenic protein production in the hAPP-J20 mouse model of AD. Female hAPP mice spent more time in estrogen-dominant cycle stages and these ovarian stages worsened AD-related network dysfunction and cognitive impairments. In contrast, progesterone-dominant stages and gonadectomy attenuated these AD-related deficits. Further studies revealed a direct role for estradiol in stimulating neural network excitability and susceptibility to seizures in hAPP mice. Understanding dynamic effects of the ovarian cycle on the female nervous system in disease, including AD, is of critical importance and may differ from effects on a healthy brain. The pattern of ovarian cycle effects on disease-related networks, cognition, and pathogenic protein expression may be relevant to young women at risk for AD.Significance Statement Alzheimer’s disease (AD) is insidious and begins several decades before clinical symptoms. For women, this means that pathophysiological changes could occur in the brain during the reproductive life-stage – prior to the cessation of ovarian function. Whether ovarian functions alter substrates of AD pathogenesis is unknown. We show that ovarian cycles are altered in a mouse model of AD and that ovarian cycle stage contributes to AD-related network and cognitive impairments. Investigating network activity, cognition, seizures, and other manifestations of brain function across the reproductive cycle stages in cycling women could reveal differential patterns in the brain at risk for AD compared to normal aging – and potentially open the door for preventative therapies and early treatment in women at risk for AD. ER -