Accelerated Ovarian Failure as a Unique Model to Study Peri-Menopause Influence on Alzheimer's Disease.

Roberta Marongiu

doi:10.3389/fnagi.2019.00242

Abstract

Despite decades of extensive research efforts, efficacious therapies for Alzheimer’s disease (AD) are lacking. The multi-factorial nature of AD neuropathology and symptomatology has taught us that a single therapeutic approach will most likely not fit all. Women constitute ~70% of the affected AD population, and pathology and rate of symptoms progression are 2–3 times higher in women than men. Epidemiological data suggest that menopausal estrogen loss may be causative of the more severe symptoms observed in AD women, however, results from clinical trials employing estrogen replacement therapy are inconsistent. AD pathological hallmarks—amyloid β (Aβ), neurofibrillary tangles (NFTs), and chronic gliosis—are laid down during a 20-year prodromal period before clinical symptoms appear, which coincides with the menopause transition (peri-menopause) in women (~45–54-years-old). Peri-menopause is marked by widely fluctuating estrogen levels resulting in periods of irregular hormone-receptor interactions. Recent studies showed that peri-menopausal women have increased indicators of AD phenotype (brain Aβ deposition and hypometabolism), and peri-menopausal women who used hormone replacement therapy (HRT) had a reduced AD risk. This suggests that neuroendocrine changes during peri-menopause may be a trigger that increases risk of AD in women. Studies on sex differences have been performed in several AD rodent models over the years. However, it has been challenging to study the menopause influence on AD due to lack of optimal models that mimic the human process. Recently, the rodent model of accelerated ovarian failure (AOF) was developed, which uniquely recapitulates human menopause, including a transitional peri-AOF period with irregular estrogen fluctuations and a post-AOF stage with low estrogen levels. This model has proven useful in hypertension and cognition studies with wild type animals. This review article will highlight the molecular mechanisms by which peri-menopause may influence the female brain vulnerability to AD and AD risk factors, such as hypertension and apolipoprotein E (APOE) genotype. Studies on these biological mechanisms together with the use of the AOF model have the potential to shed light on key molecular pathways underlying AD pathogenesis for the development of precision medicine approaches that take sex and hormonal status into account.

Highlights

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disorder and a leading cause of mortality (Alzheimer’s Association, 2016; Scheltens et al, 2016)
While the data obtained employing the aging and OVX models only suggested that estrogen plays a role in hypertension in rodents, in the studies by the Milner group, the use of the accelerated ovarian failure (AOF) model uniquely allowed the testing of the hypothesis that irregular estrogen fluctuations during AOF transition, rather than loss of estrogen at post-AOF, may be responsible for the observed increase in susceptibility to Angiotensin II (AngII)-induced hypertension
As for the studies by Acosta et al (2009, 2010) on the influence of the menopause model used in cognitive tasks, these findings indicate that distinct neurobiological processes underlie AngII-induced hypertension in aging and AOF, which may arise from the differences in estrogen levels between aged and AOF female mice

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disorder and a leading cause of mortality (Alzheimer’s Association, 2016; Scheltens et al, 2016). Besides directly influencing brain structures regulating cognitive function, hormonal and neurological changes during menopause transition may indirectly influence other risk factors that differentially affect men and women, such as APOE genotype and hypertension (see paragraph on the use of VCD mouse model to study hypertension; Nebel et al, 2018).

Results

Conclusion