Casali Brad T, Lin Li, Benedict Olesia, Zuppe Hannah, Marsico Emily, Reed Erin G
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, 4209 St. Rt. 44, Rootstown, OH, 44272, USA.
J Neuroinflammation. 2025 Mar 13;22(1):81. doi: 10.1186/s12974-025-03404-8.
Alzheimer's disease (AD) is a neurodegenerative disorder disproportionally affecting women with sex-specific disease manifestations and therapeutic responses. Microglial-mediated inflammation occurs in response to and perpetuates disease processes, and fundamental sex differences in microglia may contribute to these sex biases. Both sex chromosomes and gonad-derived hormones shape immune responses, but their contribution to immune-mediated mechanisms underlying the sex bias in AD is unclear. Crossing the Four Core Genotype (FCG) model to separate sex chromosome and gonad-derived hormone effects to the 5xFAD model, we found the sex chromosome complement impacted microgliosis, neuroinflammation, plaque burden and neuritic dystrophy. Modification of pathology largely correlated with microgliosis, and sex chromosomes and gonad-derived hormones influenced plaque remodeling and microglial CD11c expression. Our results provide potential trajectories for studying and targeting microglial-mediated sex differences and emphasize the complex interplay between sex chromosomes and hormones during AD.
阿尔茨海默病（AD）是一种神经退行性疾病，对女性的影响尤为严重，存在性别特异性的疾病表现和治疗反应。小胶质细胞介导的炎症会对疾病进程产生反应并使其持续存在，而小胶质细胞中的基本性别差异可能导致了这些性别偏差。性染色体和性腺衍生的激素都会影响免疫反应，但它们对AD中性别偏差背后的免疫介导机制的作用尚不清楚。通过四核心基因型（FCG）模型来区分性染色体和性腺衍生激素对5xFAD模型的影响，我们发现性染色体组成会影响小胶质细胞增生、神经炎症、斑块负荷和神经纤维营养不良。病理改变在很大程度上与小胶质细胞增生相关，性染色体和性腺衍生激素会影响斑块重塑和小胶质细胞CD11c的表达。我们的研究结果为研究和针对小胶质细胞介导的性别差异提供了潜在的方向，并强调了AD期间性染色体和激素之间复杂的相互作用。
