Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
Folia Neuropathol. 2024;62(2):127-135. doi: 10.5114/fn.2024.138140.
The neuroinflammation is a crucial component of virtually all neurodegenerative disorders, including Alzheimer's disease (AD). The bacterial lipopolysaccharide (LPS), a potent activator of the innate immune system, was suggested to influence or even trigger the neuropathological alterations in AD. LPS-induced neuroinflammation involves changes in transcription of several genes, thus controlling these molecular processes may be a potentially efficient strategy to attenuate the progression of AD. Since genome-wide association studies showed that the majority of AD-related genetic risk factors (AD-GRF) are connected to the immune system, our aim was to identify AD-GRF affected in the hippocampus by LPS-induced systemic inflammatory response (SIR). Moreover, we analysed the role of bromodomain and extraterminal domain (BET) proteins, the readers of the acetylation code, in controlling the transcription of selected AD-GRF in the brain during neuroinflammation. In our study, we used a mouse model of LPS-induced SIR and mouse microglial BV2 cells. JQ1 was used as an inhibitor of BET proteins. The level of mRNA was analysed using microarrays and qPCR. Our data demonstrated that among the established AD-GRF, only the expression of Cd33 was significantly upregulated in the hippocampus during SIR. In parallel, we observed an increase in the expression of Brd4, a BET family member. JQ1 prevented an LPS-evoked increase in Cd33 expression in the hippocampus of mice. Moreover, JQ1 reduced Cd33 expression in BV2 microglial cells stimulated with blood serum from LPS-treated mice. Our study suggests that LPS-evoked SIR may increase Cd33 gene expression in the brain, and inhibition of BET proteins through suppression of Cd33 expression could be a promising strategy in prevention or in slowing down the progression of neuroinflammation and may potentially affect the pathomechanism of AD.
神经炎症是几乎所有神经退行性疾病（包括阿尔茨海默病）的关键组成部分。细菌脂多糖（LPS）是先天免疫系统的有效激活剂，据推测它会影响甚至引发 AD 的神经病理改变。LPS 诱导的神经炎症涉及几个基因的转录变化，因此控制这些分子过程可能是减轻 AD 进展的潜在有效策略。由于全基因组关联研究表明，大多数与 AD 相关的遗传风险因素（AD-GRF）与免疫系统有关，我们的目标是确定 LPS 诱导的全身炎症反应（SIR）中受 AD-GRF 影响的海马区。此外，我们分析了溴结构域和末端结构域（BET）蛋白在控制大脑中选定的 AD-GRF 转录中的作用，这些蛋白是乙酰化密码的读取器，在神经炎症期间。在我们的研究中，我们使用了 LPS 诱导的 SIR 小鼠模型和小鼠小胶质细胞 BV2 细胞。JQ1 被用作 BET 蛋白的抑制剂。使用微阵列和 qPCR 分析 mRNA 水平。我们的数据表明，在已建立的 AD-GRF 中，只有 Cd33 的表达在 SIR 期间在海马体中显著上调。同时，我们观察到 BET 家族成员 Brd4 的表达增加。JQ1 可防止 LPS 诱导的 Cd33 在小鼠海马体中的表达增加。此外，JQ1 降低了由 LPS 处理的小鼠血清刺激的 BV2 小胶质细胞中 Cd33 的表达。我们的研究表明，LPS 诱导的 SIR 可能会增加大脑中 Cd33 基因的表达，通过抑制 BET 蛋白抑制 Cd33 的表达可能是预防或减缓神经炎症进展的有前途的策略，并可能影响 AD 的发病机制。
