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Reproductive Cycle May Foreshadow Alzheimer’s

Summary: A new mouse study reveals females most prone to develop Alzheimer’s disease display a unique pattern of fluctuations in sex hormones during the ovarian cycle.

Source: SfN.

Female mice destined to develop Alzheimer’s-like pathology and related cognitive impairments display a unique pattern of fluctuation in sex hormones during the ovarian cycle, finds new research published in eNeuro. This study suggests the natural reproductive cycle may provide a new window into Alzheimer’s Disease (AD) risk among young women.

AD begins to develop decades before the first clinical symptoms emerge. This means the disease may already be progressing during a woman’s reproductive years. Dena Dubal and colleagues asked whether the hormones — specifically estrogen — released during the natural ovarian cycle promote disease progression in at-risk individuals.

Despite similarities in cycle length and fertility, the researchers found AD model mice spent a greater portion of time in stages with high estrogen levels than control mice. These stages were associated with impaired learning and memory and abnormal activity in AD-affected brain regions. The researchers also observed a sharp increase in beta-amyloid production during one of the high-estrogen stages. These findings emphasize the importance of incorporating female biology into the study of nervous system disorders.

diagram

The ovarian cycle comprises different stages with fluctuating female hormones. Female mice brewing Alzheimer’s toxicity (hAPP/Abeta mice) spend more time in estrogen-dominant stages of their reproductive cycles (in brown) than their healthy, otherwise identical sisters without toxicity. With Alzheimer’s toxicity brewing, these estrogen-dominant stages promote dysfunction in brain networks and in memory. In contrast, the progesterone-dominant stages (in purple) quell the problems. Could patterns of reproductive cycles in young women predict risk for developing Alzheimer’s — or open the door for prevention and early treatment in young women at risk for the disease? NeuroscienceNews.com image is credited Arturo Moreno.

About this neuroscience research article

Funding: National Institutes of Health, American Federation for Aging Research, Alzheimer’s Association, National Science Foundation, Bakar Foundations, Coulter-Weeks Foundations funded this study.

Source: SfN
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited Arturo Moreno.
Original Research: Abstract for “Ovarian cycle stages modulate Alzheimer-related cognitive and brain network alterations in female mice” by Lauren Broestl, Kurtresha Worden, Arturo J. Moreno, Emily J. Davis, Dan Wang, Bayardo Garay, Tanya Singh, Laure Verret, Jorge J. Palop and Dena B. Dubal in eNeuro. Published December 3 2018.
doi:10.1523/ENEURO.0132-17.2018

Cite This NeuroscienceNews.com Article
SfN”Reproductive Cycle May Foreshadow Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 3 December 2018.
<http://neurosciencenews.com/alzheimers-reproductive-cycle-120194/>.
SfN(2018, December 3). Reproductive Cycle May Foreshadow Alzheimer’s. NeuroscienceNews. Retrieved December 3, 2018 from http://neurosciencenews.com/alzheimers-reproductive-cycle-120194/
SfN”Reproductive Cycle May Foreshadow Alzheimer’s.” http://neurosciencenews.com/alzheimers-reproductive-cycle-120194/ (accessed December 3, 2018).

Abstract

Ovarian cycle stages modulate Alzheimer-related cognitive and brain network alterations in female mice

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.

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