Sex Differences in Cholinergic Neurons in the Context of Alzheimer's Disease
Why are most Alzheimer's disease patients women? The longer female life expectancy is not enough to explain all of this difference, so researchers investigate the underlying biochemical differences between sexes in search of an explanation. The goal is to use this difference in outcomes to identify mechanisms that are important to disease progression in all humans. One might look at a recent paper on microglial biochemistry, for example, and compare with this examination of the activity of cholinergic neurons. It is worth noting that the two are linked, with cholinergic neurons likely regulating microglial behavior to some degree.
Several studies in mouse models of Alzheimer's disease (AD) and in cognitively normal older adults at risk for AD have consistently pointed to the selective vulnerability of cholinergic neurons to amyloid pathology as an early and critical component of presymptomatic disease which predicts subsequent neurodegenerative progression. Indeed, basal forebrain cholinergic neurons dysfunction and degeneration are early pathological events in AD that precede and predict cortical degeneration, clinical onset, and dementia severity.
There is also a close relationship between early dysfunctions in cholinergic signaling and amyloid β (Aβ) pathology. Decreased cholinergic signaling is associated with increased Aβ levels in the brain of mouse models and human patients. Furthermore, Aβ reduces acetylcholine (ACh) synthesis and release both in vitro and in vivo. Given that the brain cholinergic system of males and females show subtle functional differences and that sex hormones exert trophic effects on the cholinergic system, we hypothesized that biological sex may causally influence the relationship between cholinergic tone and amyloid pathology.
We quantified amyloid beta (Aβ) in male and female App-mutant mice with either decreased or increased cholinergic tone and examined the impact of ovariectomy and estradiol replacement in this relationship. We also investigated longitudinal changes in basal forebrain cholinergic function and Aβ in elderly individuals. We show a causal relationship between cholinergic tone and amyloid pathology in males and ovariectomized female mice, which is decoupled in ovary-intact and ovariectomized females receiving estradiol. In elderly humans, cholinergic loss exacerbates Aβ. Our findings emphasize the importance of reflecting human menopause in mouse models. They also support a role for therapies targeting estradiol and cholinergic signaling to reduce Aβ.
Also...
When women enter menopause, usually in their late 40s or early 50s, their estrogen levels decrease significantly.
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Research suggests that estrogen has neuroprotective effects on the brain. It helps maintain healthy brain function, including memory, cognition, and mood regulation. Estrogen also supports the health of brain cells and promotes the formation of new neural connections.
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Estrogen deficiency, which occurs during and after menopause, has been associated with an increased risk of cognitive decline, memory problems, and a higher likelihood of developing neurodegenerative disorders such as Alzheimer's disease. Some studies indicate that hormone replacement therapy (HRT), which involves supplementing estrogen and sometimes progesterone, can help mitigate these risks in postmenopausal women.
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While both men and women experience hormonal changes with age, the decline in estrogen levels in women after menopause is more abrupt and significant, which might contribute to a more noticeable impact on brain health.