PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：年龄和性别是发生迟发性阿尔茨海默病的主要危险因素。和男人相比,尽管患有这种疾病的女性寿命更长，但她们的神经病理学负担和认知能力下降。同样，雄性3xTg-AD小鼠，开发为阿尔茨海默病模型，不再持续表现出标准的阿尔茨海默氏症神经病理学，但经历更高的死亡率-提供了一个独特的机会来进一步阐明这一二分法。我们假设生物衰老过程中的性别差异在男性和女性中产生不同的病理和分子阿尔茨海默病特征，可用于治疗和生物标志物开发。
方法：我们男女年龄，3xTg-AD和B6129对照小鼠在各自的寿命(n=3-8只小鼠/性别,应变，和年龄组）并纵向评估阿尔茨海默病的神经病理学标志，肝脏炎症的标志物，脾质量和形态，以及血浆细胞因子水平。我们对大量脑组织进行了RNA测序分析，并检查了3xTg-AD和B6129样品之间以及每种性别年龄之间的差异表达基因（DEG）。我们还检查了来自西奈山脑库研究的临床阿尔茨海默氏症和对照海马旁回脑组织样本之间的DEG。
结果：3xTg-AD女性的寿命明显超过3xTg-AD男性，并表现出进行性阿尔茨海默病的神经病理学，而3xTg-AD男性表现出进行性肝脏炎症，脾肿大,循环炎症蛋白，和轻微的老年痴呆症的神经病理学标志。相反，相对于女性,3xTg-AD男性经历了脑中免疫相关基因表达的加速上调。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发生了类似的性别特异性改变。在这两个物种的患病雄性中，我们观察到补体相关基因表达上调，脂多糖被预测为DEGs的最高上游调节剂。
结论：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有助于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引发了3xTg-AD男性的广泛炎症反应，尽管没有感染，但模拟了脂多糖刺激的影响。
方法：我们男女年龄，3xTg-AD和B6129对照小鼠在各自的寿命(n=3-8只小鼠/性别,应变，和年龄组）并纵向评估阿尔茨海默病的神经病理学标志，肝脏炎症的标志物，脾质量和形态，以及血浆细胞因子水平。我们对大量脑组织进行了RNA测序分析，并检查了3xTg-AD和B6129样品之间以及每种性别年龄之间的差异表达基因（DEG）。我们还检查了来自西奈山脑库研究的临床阿尔茨海默氏症和对照海马旁回脑组织样本之间的DEG。
结果：3xTg-AD女性的寿命明显超过3xTg-AD男性，并表现出进行性阿尔茨海默病的神经病理学，而3xTg-AD男性表现出进行性肝脏炎症，脾肿大,循环炎症蛋白，和轻微的老年痴呆症的神经病理学标志。相反，相对于女性,3xTg-AD男性经历了脑中免疫相关基因表达的加速上调。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发生了类似的性别特异性改变。在这两个物种的患病雄性中，我们观察到补体相关基因表达上调，脂多糖被预测为DEGs的最高上游调节剂。
结论：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有助于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引发了3xTg-AD男性的广泛炎症反应，尽管没有感染，但模拟了脂多糖刺激的影响。
