Summary: Early postmenopausal estrogen replacement may reduce the risk of Alzheimer’s disease in some women.
Source: IOS Press
Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. It disproportionately affects women. A recent study published in the Journal of Alzheimer’s Disease highlights how factors such as age, reproductive status, hormone levels and their interaction with other risk factors may influence women’s risk of AD. The research proposes that early estrogen replacement after menopause could help protect some women from developing AD-related changes.
“The risk, progression and clinical severity of Alzheimer’s disease differ between men and women,” said co-lead investigator Elena Tamagno, PhD, Department of Neuroscience, Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Italy. “Epidemiological data show that about two thirds of AD patients are women, a difference that cannot be explained solely by women’s longer life expectancy. Loss of estradiol after menopause may contribute to cognitive decline in women.”
Two pathological hallmarks define AD: extracellular deposits of amyloid beta peptides forming plaques, and intracellular aggregation of altered tau protein into neurofibrillary tangles. Tau normally stabilizes microtubules in neurons, but in AD it becomes abnormally modified and aggregated. To investigate whether biological sex alters how amyloid beta 42 (Aβ42) peptides affect tau, the researchers injected nanomolar concentrations of Aβ42 into the brain ventricles of transgenic mice that express human wild-type tau (hTau). A prior study by the team had observed that intact female mice were resistant to the tau alterations typically seen in AD. In the current work, they found that Aβ42 induced pathological tau changes in ovariectomized female mice but not in intact control females. Importantly, estradiol replacement in the ovariectomized mice prevented these tau changes, an effect linked to antioxidant activity and reduced tau phosphorylation.
“Our findings indicate that age, reproductive stage, hormone levels and their interaction with other risk factors need to be considered when evaluating women’s risk and planning preventive strategies for cognitive decline,” commented co-lead investigator Massimo Tabaton, MD, Unit of Geriatric Medicine, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Italy. “The results support the possibility that initiating estrogen replacement early in the postmenopausal period may offer protection against Alzheimer’s-related tau pathology.”
“Connecting estrogen deficiency to the tau abnormalities seen in Alzheimer’s provides an important mechanistic link that helps explain the higher AD risk in women and points to potential therapeutic strategies,” added George Perry, PhD, Editor-in-Chief of the Journal of Alzheimer’s Disease and Semmes Foundation Distinguished University Chair in Neurobiology at The University of Texas at San Antonio.
Alzheimer’s disease is a major public health and social challenge. In the United States roughly 5.5 million people currently live with AD, and as populations age this number continues to rise. Worldwide estimates place dementia prevalence at about 24 million people, with projections suggesting this figure could double by 2050. AD typically begins with decline in the ability to form new memories and gradually impairs all cognitive domains, ultimately causing loss of independence in daily activities and premature death. Women face a higher lifetime risk of developing AD independent of greater longevity: about one in six women over age 65 develops AD, compared with one in eleven men.
About this dementia research article
Source:
IOS Press
Contacts:
Diana Murray – IOS Press
Image Source:
The image is in the public domain.
Original Research:
Closed access
“Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice” by Elena Tamagno et al., Journal of Alzheimer’s Disease.
Abstract
Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice
Background:
Male and female individuals show different risks and clinical trajectories for Alzheimer’s disease. Cognitive decline can be more pronounced in women at comparable disease stages, and estradiol levels may contribute to this disparity. This study examined how biological sex modifies the impact of amyloid-β42 (Aβ42) monomers on tau’s pathological conformational changes.
Methods:
Researchers used transgenic hTau mice that express human wild-type tau and administered intraventricular (ICV) injections of Aβ peptides at nanomolar concentrations to assess resulting changes in tau conformation and phosphorylation.
Results:
Aβ42 induced pathological conformational changes and hyperphosphorylation of tau in male mice and in ovariectomized females, but not in intact control females. Estradiol replacement in ovariectomized females prevented the pathological tau conformation. The protective effect appears to involve antioxidant mechanisms and modulation of miRNA-218, a regulator linked to tau phosphorylation.
Conclusion:
These findings emphasize that age, reproductive status, hormone levels and their interaction with other risk factors should be taken into account when identifying preventive and therapeutic strategies for cognitive decline in women. The data suggest that appropriately timed estrogen replacement after menopause could be protective against Alzheimer’s-related tau pathology in some women.