Department of Neurology, Geisel School of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Alzheimers Res Ther. 2024 Jun 22;16(1):134. doi: 10.1186/s13195-024-01492-x.
Aging and sex are major risk factors for developing late-onset Alzheimer's disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer's disease, no longer consistently exhibit standard Alzheimer's neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer's disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.
We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans (n = 3-8 mice per sex, strain, and age group) and longitudinally assessed neuropathological hallmarks of Alzheimer's disease, markers of hepatic inflammation, splenic mass and morphology, as well as plasma cytokine levels. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and B6129 samples and across ages in each sex. We also examined DEGs between clinical Alzheimer's and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank study in each sex.
3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer's neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and minimal Alzheimer's neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females. Our clinical investigations revealed that individuals with Alzheimer's disease develop similar sex-specific alterations in neuronal and immune function. In diseased males of both species, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide was predicted as the top upstream regulator of DEGs.
Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, indicating that age-related changes in immune response contribute to sex differences in Alzheimer's disease trajectories. We provide evidence that aging and transgene-driven disease progression trigger a widespread inflammatory response in 3xTg-AD males, which mimics the impact of lipopolysaccharide stimulation despite the absence of infection.
衰老和性别是导致迟发性阿尔茨海默病的主要危险因素。与男性相比，尽管女性患有这种疾病的时间更长，但她们的神经病理学负担和认知能力下降更为严重。同样，为模拟阿尔茨海默病而开发的雄性 3xTg-AD 小鼠不再一致表现出标准的阿尔茨海默氏神经病理学，但死亡率更高——为进一步阐明这种二分法提供了独特的机会。我们假设，生物衰老过程中的性别差异会导致男性和女性的阿尔茨海默病的病理和分子特征明显不同，这可以为治疗和生物标志物的发展提供依据。
我们对雄性和雌性 3xTg-AD 和 B6129 对照小鼠进行了跨代的老化研究（每个性别、品系和年龄组各有 3-8 只小鼠），并对阿尔茨海默病的神经病理学标志、肝炎症标志物、脾质量和形态以及血浆细胞因子水平进行了纵向评估。我们对大脑组织进行了 RNA 测序分析，并检查了 3xTg-AD 和 B6129 样本之间以及每个性别中随年龄变化的差异表达基因 (DEG)。我们还检查了来自西奈山大脑库研究的男女两性临床阿尔茨海默病和对照海马旁回脑组织样本之间的 DEG。
3xTg-AD 雌性小鼠的寿命明显长于 3xTg-AD 雄性小鼠，并表现出进行性阿尔茨海默病神经病理学变化，而 3xTg-AD 雄性小鼠则表现出进行性肝炎症、脾肿大、循环炎症蛋白和最小的阿尔茨海默病神经病理学标志。相反，3xTg-AD 雄性小鼠的大脑中与免疫相关的基因表达上调速度快于雌性小鼠。我们的临床研究表明，患有阿尔茨海默病的个体在神经元和免疫功能方面表现出相似的性别特异性改变。在两种物种的患病雄性中，我们观察到补体相关基因表达的上调幅度更大，脂多糖被预测为 DEG 的顶级上游调节剂。
我们的数据表明，慢性炎症和补体激活与死亡率增加有关，这表明与年龄相关的免疫反应变化导致了阿尔茨海默病轨迹的性别差异。我们提供的证据表明，衰老和转基因驱动的疾病进展在 3xTg-AD 雄性中引发了广泛的炎症反应，尽管没有感染，但这种反应类似于脂多糖刺激的影响。
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