Department of Pharmacology and Toxicology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
J Alzheimers Dis. 2023;94(4):1361-1375. doi: 10.3233/JAD-220905.
Nearly two-thirds of patients diagnosed with Alzheimer's disease (AD) are female. In addition, female patients with AD have more significant cognitive impairment than males at the same disease stage. This disparity suggests there are sex differences in AD progression. While females appear to be more affected by AD, most published behavioral studies utilize male mice. In humans, there is an association between antecedent attention-deficit/hyperactivity disorder and increased risk of dementia. Functional connectivity studies indicate that dysfunctional cortico-striatal networks contribute to hyperactivity in attention deficit hyperactivity disorder. Higher plaque density in the striatum accurately predicts the presence of clinical AD pathology. In addition, there is a link between AD-related memory dysfunction and dysfunctional dopamine signaling.
With the need to consider sex as a biological variable, we investigated the influence of sex on striatal plaque burden, dopaminergic signaling, and behavior in prodromal 5XFAD mice.
Six-month-old male and female 5XFAD and C57BL/6J mice were evaluated for striatal amyloid plaque burden, locomotive behavior, and changes in dopaminergic machinery in the striatum.
5XFAD female mice had a higher striatal amyloid plaque burden than male 5XFAD mice. 5XFAD females, but not males, were hyperactive. Hyperactivity in female 5XFAD mice was associated with increased striatal plaque burden and changes in dopamine signaling in the dorsal striatum.
Our results indicate that the progression of amyloidosis involves the striatum in females to a greater extent than in males. These studies have significant implications for using male-only cohorts in the study of AD progression.
近三分之二被诊断患有阿尔茨海默病（AD）的患者为女性。此外，处于相同疾病阶段的女性 AD 患者的认知障碍比男性更为严重。这种差异表明 AD 的进展存在性别差异。尽管女性似乎更容易受到 AD 的影响，但大多数已发表的行为研究都使用雄性小鼠。在人类中，注意力缺陷多动障碍（ADHD）的前期存在与痴呆风险增加有关。功能连接研究表明，皮质纹状体网络功能障碍导致 ADHD 中的过度活跃。纹状体中的斑块密度越高，准确预测临床 AD 病理的存在。此外，AD 相关的记忆功能障碍与多巴胺信号传导功能障碍之间存在联系。
由于需要将性别视为生物学变量，因此我们研究了性别对 AD 前驱期 5XFAD 小鼠纹状体斑块负担、多巴胺能信号传导和行为的影响。
对 6 月龄雄性和雌性 5XFAD 和 C57BL/6J 小鼠进行纹状体淀粉样斑块负担、运动行为以及纹状体多巴胺机制变化的评估。
5XFAD 雌性小鼠的纹状体淀粉样斑块负担高于雄性 5XFAD 小鼠。只有雌性 5XFAD 小鼠表现出过度活跃，而雄性 5XFAD 小鼠则没有。雌性 5XFAD 小鼠的过度活跃与纹状体斑块负担增加以及背侧纹状体多巴胺信号变化有关。
我们的研究结果表明，淀粉样蛋白病变的进展在女性中比在男性中更涉及纹状体。这些研究对仅使用雄性队列来研究 AD 进展具有重要意义。
