Abstract
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 cycle 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 and increasing amyloid beta levels. 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.
Footnotes
The authors declare no competing financial interests.
This work was supported by the U.S. National Institutes of Health (NIH) AG034531 (D.B.D.), R01NS092918 (D.B.D.), R01AG047313 (J.J.P.), RF1AG062234 (J.J.P.), American Federation for Aging Research (D.B.D.), Alzheimer’s Association Grant (J.J.P.), National Science Foundation grant 1650113 (E.J.D.), and the Bakar Foundation (D.B.D.) and Coulter-Weeks (D.B.D.) Foundation. All animal studies were approved by the Institutional Animal Care and Use Committee of the University of California, San Francisco and conducted in compliance with NIH guidelines. We thank the Gladstone Institutes’ Behavioral Core, including N. Devidze and I. Lo for technical assistance, and D. Glidden and L. Bonham for assistance with statistical analyses.
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