Endogenous and Exogenous Estrogen Exposures: How Women's Reproductive Health Can Drive Brain Aging and Inform Alzheimer's Prevention.

After advanced age, female sex is the major risk factor for late-onset Alzheimer's disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10-20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17ß-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.

Enteroinvasive Escherichia coli O96:H19 is an Emergent Biofilm-Forming Pathogen.

Enteroinvasive Escherichia coli (EIEC) is a diarrheagenic E. coli pathotype carrying a virulence plasmid that encodes a type III secretion system (TTSS) directly implicated in bacterial cell invasion. Since 2012, EIEC serotype O96:H19 has been recognized in Europe, Colombia, and most recently Uruguay. In addition to the invasion phenotype, the strains isolated from Colombian children with moderate-to-severe gastroenteritis had a strong biofilm formation phenotype, and as a result, they are referred to as biofilm-forming enteroinvasive E. coli (BF-EIEC). The objective of this study was to characterize the biofilm formation phenotype of the BF-EIEC O96:H19 strain 52.1 isolated from a child with moderate-to-severe gastroenteritis in Colombia. Random mutagenesis using Tn5 transposons identified 100 mutants unable to form biofilm; 20 of those had mutations within the pgaABCD operon. Site-directed mutagenesis of pgaB and pgaC confirmed the importance of these genes in N-acetylglucosamine-mediated biofilm formation. Both biofilm formation and TTSS-mediated host cell invasion were associated with host cell damage on the basis of cytotoxic assays comparing the wild type, invasion gene mutants, and biofilm formation mutants. Multilocus sequence typing-based phylogenetic analysis showed that BF-EIEC strain 52.1 does not cluster with classic EIEC serotype strains. Instead, BF-EIEC strain 52.1 clusters with EIEC serotype O96:H19 strains described in Europe and Uruguay. In conclusion, BF-EIEC O96:H19, an emerging pathogen associated with moderate-to-severe acute gastroenteritis in children under 5 years of age in Colombia, invades cells and has a strong biofilm formation capability. Both phenotypes are independently associated with in vitro cell cytotoxicity, and they may explain, at least in part, the higher disease severity reported in Europe and Latin America. IMPORTANCE Enteroinvasive Escherichia coli (EIEC), a close relative of Shigella, is implicated in dysenteric diarrhea. EIEC pathogenicity involves cell invasion mediated by effector proteins delivered by a type III secretion system (TTSS) that disrupt the cell cytoskeleton. These proteins and the VirF global regulator are encoded by a large (>200 kb) invasion plasmid (pINV). This study reports an emergent EIEC possessing a cell invasion phenotype and a strong polysaccharide matrix-mediated biofilm formation phenotype. Both phenotypes contribute to host cell cytotoxicity in vitro and may contribute to the severe disease reported among children and adults in Europe and Latin America.

Association of Reproductive History With Brain MRI Biomarkers of Dementia Risk in Midlife.

BACKGROUND AND OBJECTIVES: To examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife. METHODS: We evaluated 99 cognitively normal women 52 ± 6 years of age and 29 men 52 ± 7 years of age with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations among reproductive history indicators, voxel-wise gray matter volume (GMV), and memory and global cognition scores, adjusting for demographics and midlife health indicators. Exposure variables were menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, and use of menopause hormonal therapy (HT) and hormonal contraceptives (HC). RESULTS: All menopausal groups exhibited lower GMV in AD-vulnerable regions compared to men, with perimenopausal and postmenopausal groups also exhibiting lower GMV in temporal cortex compared to the premenopausal group. Reproductive span, number of children and pregnancies, and use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE ε4 status, and midlife health indicators. Although reproductive history indicators were not directly associated with cognitive measures, GMV in temporal regions was positively associated with memory and global cognition scores. DISCUSSION: Reproductive history events signaling more estrogen exposure such as premenopausal status, longer reproductive span, higher number of children, and use of HT and HC were associated with larger GMV in women in midlife. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD risk.