Schultz Bruna, Bobermin Larissa, Menezes Leonardo, Gayger-Dias Vitor, Da Silva Vanessa-Fernanda, Taday Jéssica, Alves Joelma, Tramontina Francine, Zanotto Caroline, Dalmaz Carla, Leite Marina Concli, Leal Rodrigo Bainy, Quincozes-Santos André, Gonçalves Carlos-Alberto
Graduate Program in Biochemistry, Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos Street 2600 Biochemistry Building Laboratory 33, Porto Alegre, RS, 90035-003, Brazil.
Universidade Estadual do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Neurobiol. 2025 May 15. doi: 10.1007/s12035-025-05046-6.
Although the causes of Alzheimer's disease (AD) are still unknown, the unfolded protein response (UPR) is considered the basis for the pathogenesis of many degenerative diseases, including AD. The incidence of AD is slightly higher in the female population; however, biases continue to raise questions as to whether gender is a risk factor for the disease, as insulin resistance is. In this study, we used a sporadic model of Alzheimer's disease, induced by intracerebroventricularly-administered streptozotocin (STZ) in Wistar rats, to evaluate potential modulations in proteins involved in the UPR and the dependence of alterations on the sex of the animals. The rats were evaluated at two time points; 4 and 16 weeks post-STZ. At 16 weeks, cognitive deficit was observed in all rats treated with STZ, as well as an increase in glial fibrillary acid protein (GFAP), and a reduction in synaptophysin in the hippocampus. However, at 4 weeks, cognitive deficit was found only in males, in association with a reduction in synaptophysin. With regard to neurochemical changes in the AD model of STZ, we found sex-dependent differences in the gene expression of OASIS (an ATF-6-like UPR sensor in astrocytes), calpastatin (inhibitor protein of calpain 1/2), calpain-10, calcineurin, sorcin and CHOP. Taken together, results obtained herein contribute to the understanding of the pathogenesis of AD and indicate that the STZ-triggered UPR observed may be sex-dependent.
尽管阿尔茨海默病（AD）的病因仍不明，但未折叠蛋白反应（UPR）被认为是包括AD在内的许多退行性疾病发病机制的基础。AD在女性人群中的发病率略高；然而，如同胰岛素抵抗一样，性别是否为该疾病的风险因素，这种偏差仍引发诸多疑问。在本研究中，我们使用了Wistar大鼠脑室内注射链脲佐菌素（STZ）诱导的散发性阿尔茨海默病模型，以评估UPR相关蛋白的潜在调节作用以及这些改变对动物性别的依赖性。在两个时间点对大鼠进行评估，即STZ注射后4周和16周。在16周时，所有接受STZ治疗的大鼠均出现认知缺陷，同时海马中胶质纤维酸性蛋白（GFAP）增加，突触素减少。然而，在4周时，仅在雄性大鼠中发现认知缺陷，并伴有突触素减少。关于STZ诱导的AD模型中的神经化学变化，我们发现了OASIS（星形胶质细胞中一种类似ATF-6的UPR传感器）、钙蛋白酶抑制蛋白（钙蛋白酶1/2的抑制蛋白）、钙蛋白酶-10、钙调神经磷酸酶、亲环蛋白和CHOP基因表达的性别依赖性差异。综上所述，本文获得的结果有助于理解AD的发病机制，并表明观察到的STZ触发的UPR可能具有性别依赖性。
