Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Neuroscience program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Alzheimers Dement. 2024 Feb;20(2):995-1012. doi: 10.1002/alz.13481. Epub 2023 Oct 17.
About two-thirds of Alzheimer's Disease (AD) patients are women, who exhibit more severe pathology and cognitive decline than men. Whether biological sex causally modulates the relationship between cholinergic signaling and amyloid pathology remains unknown.
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.
Cholinergic tone regulates amyloid beta (Aβ) pathology in males and ovariectomized female mice. Estradiol uncouples the relationship between cholinergic tone and Aβ. In elderly humans, cholinergic loss correlates with increased Aβ in both sexes.
大约三分之二的阿尔茨海默病（AD）患者为女性，她们的病理表现和认知能力下降比男性更为严重。生物性别是否会影响胆碱能信号与淀粉样蛋白病理之间的关系尚不清楚。
我们在具有降低或增加胆碱能张力的 App 突变雄性和雌性小鼠中定量了淀粉样蛋白β（Aβ），并研究了在这种关系中卵巢切除术和雌二醇替代的影响。我们还研究了老年个体中基底前脑（胆碱能功能）和 Aβ的纵向变化。
我们在雄性和去卵巢雌性小鼠中显示了胆碱能张力与淀粉样蛋白病理之间的因果关系，这种关系在卵巢完整和接受雌二醇的去卵巢雌性小鼠中被分离。在老年人群中，胆碱能丧失会加重 Aβ。
我们的发现强调了在小鼠模型中反映人类更年期的重要性。它们还支持针对雌二醇和胆碱能信号的治疗方法来减少 Aβ。
胆碱能张力调节雄性和去卵巢雌性小鼠中的淀粉样蛋白β（Aβ）病理。雌二醇使胆碱能张力与 Aβ 之间的关系脱钩。在老年人群中，男女两性的胆碱能丧失与 Aβ 增加相关。
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