Department of Neurology, Oregon Health and Science University, Portland, OR, United States of America; Parkinson's Disease Research, Education, and Clinical Center, Portland Veterans Affairs Medical Center, Portland, OR, United States of America.
Department of Chemical Physiology and Biochemistry, OHSU, Portland, OR, United States of America.
Neurobiol Dis. 2022 Nov;174:105888. doi: 10.1016/j.nbd.2022.105888. Epub 2022 Oct 6.
Based on previous evidence that the non-steroidal estrogen receptor modulator STX mitigates the effects of neurotoxic Amyloid-β (Aβ) in vitro, we have evaluated its neuroprotective benefits in a mouse model of Alzheimer's disease. Cohorts of 5XFAD mice, which begin to accumulate cerebral Aβ at two months of age, were treated with orally-administered STX starting at 6 months of age for two months. After behavioral testing to evaluate cognitive function, biochemical and immunohistochemical assays were used to analyze key markers of mitochondrial function and synaptic integrity. Oral STX treatment attenuated Aβ-associated mitochondrial toxicity and synaptic toxicity in the brain, as previously documented in cultured neurons. STX also moderately improved spatial memory in 5XFAD mice. In addition, STX reduced markers for reactive astrocytosis and microgliosis surrounding amyloid plaques, and also unexpectedly reduced overall levels of cerebral Aβ in the brain. The neuroprotective effects of STX were more robust in females than in males. These results suggest that STX may have therapeutic potential in Alzheimer's Disease.
基于先前的证据表明，非甾体雌激素受体调节剂 STX 可以减轻体外神经毒性淀粉样蛋白-β（Aβ）的作用，我们评估了其在阿尔茨海默病小鼠模型中的神经保护作用。从两个月大开始在大脑中积累 Aβ的 5XFAD 小鼠被给予口服 STX 治疗，从 6 个月大开始持续两个月。在进行了评估认知功能的行为测试后，使用生物化学和免疫组织化学分析方法来分析线粒体功能和突触完整性的关键标志物。正如先前在培养神经元中所记录的那样，口服 STX 治疗减轻了大脑中与 Aβ相关的线粒体毒性和突触毒性。STX 还适度改善了 5XFAD 小鼠的空间记忆。此外，STX 减少了围绕淀粉样斑块的反应性星形胶质细胞和小胶质细胞的标志物，并且出人意料地降低了大脑中总的 Aβ水平。STX 的神经保护作用在雌性中比在雄性中更为显著。这些结果表明，STX 可能具有治疗阿尔茨海默病的潜力。
