PDF(Pubmed)
Abstract：
Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer\'s disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.
摘要：
前列腺癌的雄激素剥夺治疗（ADT）与痴呆症的风险增加有关，包括阿尔茨海默病（AD）。前列腺癌患者ADT与AD相关认知障碍之间的机制联系仍然难以捉摸。我们建立了临床相关的前列腺癌AD小鼠模型来探索这一点。荷瘤和ADT均诱导外周血和脑中免疫和炎症反应的复杂变化。ADT破坏血脑屏障（BBB）的完整性并促进免疫细胞渗入大脑，增强神经炎症和神经胶质增生，而不影响淀粉样蛋白斑块负荷。此外，用那他珠单抗治疗，FDA批准的靶向外周免疫细胞浸润的药物，在该模型中减少神经炎症并改善认知功能。我们的研究揭示了一种炎症机制，超越淀粉样蛋白病理学，这是ADT加剧的认知缺陷的基础，并提示那他珠单抗可作为减轻ADT对认知的有害影响的潜在有效治疗方法。
