A woman's risk for stroke increases exponentially following the onset of menopause; however, the underlying mechanisms responsible for the increased risk remain unknown. The depletion of endogenous estrogen at menopause is known to activate the inflammatory response. Therefore, in this study we have used reproductively senescent (RS) rats to test the hypotheses that (1) inflammasome activation is significantly higher in the brain of RS females (RSF) as compared to their younger counterparts and age-matched senescent male rats, and that (2) RS triggers an innate immune response mediated in part by inflammasome-containing extracellular vesicles (EV) that originate in the female reproductive organs and then spreads to the brain. We tested these hypotheses using male and female Sprague-Dawley rats (Young: 6-7 months and RS: 9-13 months). Hippocampus, gonads and serum were collected. Additionally, cerebrospinal fluid (CSF) of pre- and post-menopausal women (ages 23 to 37 and 52 to 68) was purchased and extracellular vesicles (EV) were isolated from serum and CSF. The Inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and IL-1β were then resolved by immunoblotting. We found that inflammasome protein expression increased significantly in the analyzed tissues in RSF as compared to young females (YF), such difference was not present in age-matched male rat brains. Interestingly, we found that Nik-related kinase (NRK), which is present in female reproductive organs was present in the CSF and serum-derived EV, suggesting that the source of the EV seen in the brain during RS/menopause originate, in part, in the female reproductive organs. Thus, this study shows for the first time an involvement of the inflammasome originating in the female reproductive system as a contributor to inflammation in the brain that makes the peri-menopausal women's brain more susceptible to neurodegenerative diseases such as stroke.

中文翻译：

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含炎性小体的细胞外囊泡中的性二态性和生殖衰老女性大脑中先天免疫的调节。

绝经期开始后，女性患中风的风险成倍增加。但是，导致风险增加的潜在机制仍然未知。绝经期内源性雌激素的消耗可激活炎症反应。因此，在这项研究中，我们使用了生殖衰老（RS）大鼠来检验以下假设：（1）与雌性同龄雌性和年龄相同的衰老雄性大鼠相比，雌性（RSF）雌性大脑中的炎性小体活化明显更高， （2）RS触发了一种先天免疫反应，这种免疫反应部分地由含炎症小体的细胞外小泡（EV）介导，该小泡起源于女性生殖器官，然后扩散到大脑。我们使用雄性和雌性Sprague-Dawley大鼠（年轻：6-7个月，RS：9-13个月）测试了这些假设。收集海马，性腺和血清。此外，购买了绝经前和绝经后妇女（23至37岁和52至68岁）的脑脊液（CSF），并从血清和CSF中分离出了细胞外囊泡（EV）。然后通过免疫印迹法分离炎性体蛋白caspase-1，含有caspase募集域（ASC）和IL-1β的凋亡相关斑点样蛋白。我们发现，与年轻雌性（YF）相比，RSF中被分析的组织中炎症小体蛋白表达显着增加，这种差异在年龄匹配的雄性大鼠脑中不存在。有趣的是，我们发现女性生殖器官中存在的Nik相关激酶（NRK）存在于CSF和血清来源的EV中，这表明在RS /绝经期大脑中看到的EV的来源部分，在女性生殖器官中。因此，这项研究首次显示出起源于女性生殖系统的炎症小体是导致大脑炎症的因素，使绝经前后妇女的大脑更容易患中风等神经退行性疾病。