Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-003, Brazil.
Lab Calcium Binding Proteins in CNS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, Bairro Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
Mol Neurobiol. 2020 Jan;57(1):502-512. doi: 10.1007/s12035-019-01718-2. Epub 2019 Aug 6.
Although the pathogenesis of Alzheimer's disease (AD) remains unclear, some molecular aspects that precede or accompany the deposit of β-amyloid in senile plaques attract attention, such as calcium dysregulation and neuroinflammation. It has been suggested that the Ca/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in AD pathogenesis. We hypothesized that CaN activation is involved in the inflammatory changes observed in the streptozotocin (STZ)-induced model of AD. We investigated hippocampal inflammatory and CaN changes in Wistar rats in two moments after intracerebroventricular STZ administration: in the first week (early) and fourth week (later on). We found an early (at 1 week) and persistent (at fourth week) increment in the subunit A of CaN, as well as an increase in the major 48 kDa fragment of this subunit. Glial and inflammatory activation were confirmed by changes of IBA-1, TLR-4, glial fibrillary acidic protein (GFAP), and S100B in the hippocampus. Augmented CaN activity was accompanied by reduced phosphorylation of the pro-apoptotic protein BAD, at Ser 136. Importantly, we found an increase in the nuclear translocation of NFAT4 (more associated to astroglial reactivity) in the hippocampus at 1 and 4 weeks in this model. NFAT3 (more associated with neuronal activation) exhibited an early increase, but decreased later on. Taken together, these data contribute to the understanding of neurochemical changes in the STZ model of sporadic AD, and may explain the persistent inflammatory response in AD, which might occur via the proteolytic activation of CaN, and signaling of NFAT mediated by isoform 4, in activated astrocytes.
虽然阿尔茨海默病（AD）的发病机制仍不清楚，但一些在β-淀粉样蛋白沉积之前或伴随其沉积的分子方面引起了人们的关注，如钙失调和神经炎症。有人认为，钙/钙调蛋白依赖性蛋白磷酸酶，钙调神经磷酸酶（CaN），在 AD 发病机制中发挥重要作用。我们假设 CaN 的激活参与了在链脲佐菌素（STZ）诱导的 AD 模型中观察到的炎症变化。我们研究了 Wistar 大鼠在侧脑室注射 STZ 后两个时间点的海马炎症和 CaN 变化：第一周（早期）和第四周（晚期）。我们发现 CaN 的亚基 A 早期（第 1 周）和持续（第 4 周）增加，以及该亚基的主要 48 kDa 片段增加。通过海马中 IBA-1、TLR-4、胶质纤维酸性蛋白（GFAP）和 S100B 的变化证实了胶质和炎症的激活。CaN 活性增强伴随着促凋亡蛋白 BAD 的 Ser 136 磷酸化减少。重要的是，我们发现该模型中海马中 NFAT4 的核易位在第 1 周和第 4 周增加（更多与星形胶质细胞反应性相关）。NFAT3（更多与神经元激活相关）早期增加，但后来减少。综上所述，这些数据有助于理解 STZ 诱导的散发性 AD 模型中的神经化学变化，并可能解释 AD 中持续的炎症反应，这可能是通过 CaN 的蛋白水解激活，以及 NFAT 介导的信号转导，在激活的星形胶质细胞中发生的。
