Gan Qini, Wong Alfred, Zhang Zhengrong, Na Hana, Tian Hua, Tao Qiushan, Rajab Ibraheem M, Potempa Lawrence A, Qiu Wei Qiao
Department of Pharmacology and Experimental Therapeutics Boston University School of Medicine Boston Massachusetts USA.
Department of Pharmacology Xiaman Medical College Xiaman People's Republic of China.
Alzheimers Dement (N Y). 2022 Jul 8;8(1):e12319. doi: 10.1002/trc2.12319. eCollection 2022.
Human study shows that elevated C-reactive protein (CRP) in blood impacts apolipoprotein E () ε4, but not ε3 or ε2, genotype to increase the risk of Alzheimer's disease (AD). However, whether CRP is directly involved in cellular AD pathogenesis and in which type of neuronal cells of ε4 carriers are unknown.
We aimed to use different primary neuronal cells and investigate if CRP induces cellular AD pathology depending on genotypes. Here the different primary neuronal cells from the different genotype knock-in mice cortex were isolated and used.
Monomeric CRP (mCRP) increased amyloid beta production and, in parallel, induced tau phosphorylation in addition to their related proteins in the primary neurons in a pattern of ε4 > ε3 > ε2 in a dose- and time-dependent manner. Consistently, mCRP induced the staining of other neurodegenerative biomarkers, including Fluoro-Jade B stain (FjB), TUNEL and Cleaved Caspase-3, in primary neurons in a similar pattern of ε4 > ε3 > ε2. In contrast, pentameric CRP (pCRP) had a tendency to induce cellular AD pathology but did not reach statistical significance. On the other hand, it is intriguing that regardless of genotype, mCRP did not influence the expressions of Iba-1 and CD68 in primary microglia or the expression of glial fibrillary acidic protein in primary astrocytes, and additionally mCRP did not affect the secretions of interleukin (IL)-1α, IL-1β, and tumor necrosis factor α from these cells.
This is the first report to demonstrate that mCRP directly induces cellular AD pathogenesis in neurons in an genotype-dependent pattern, suggesting that mCRP plays a role as a mediator involved in the ε4-related pathway for AD during chronic inflammation.
Pentameric C-reactive protein (pCRP) can be dissociated irreversibly to form free subunits or monomeric CRP (mCRP) during and after the acute phase.mCRP increased amyloid beta production in the primary neurons in a pattern of apolipoprotein E () ε4 > ε3 > ε2 in a dose-dependent manner.mCRP induced the expression of phosphorylated tau in the primary neurons in a pattern of ε4 > ε3 > ε2 in a dose- and time-dependent manner.mCRP plays an important mediator role in the ε4-related pathway of Alzheimer's disease risk.
人体研究表明，血液中C反应蛋白（CRP）水平升高会影响载脂蛋白E（ApoE）ε4基因型，但不影响ε3或ε2基因型，从而增加患阿尔茨海默病（AD）的风险。然而，CRP是否直接参与细胞AD发病机制以及ε4携带者的哪种神经元细胞类型中CRP起作用尚不清楚。
我们旨在使用不同的原代神经元细胞，并研究CRP是否根据ApoE基因型诱导细胞AD病理变化。这里分离并使用了来自不同ApoE基因型敲入小鼠皮质的不同原代神经元细胞。
单体CRP（mCRP）以剂量和时间依赖性方式增加原代神经元中淀粉样β蛋白的产生，同时，除了其相关蛋白外，还诱导tau蛋白磷酸化，其模式为ε4>ε3>ε2。一致地，mCRP以类似的ε4>ε3>ε2模式在原代神经元中诱导其他神经退行性生物标志物的染色，包括氟玉红B染色（FjB）、TUNEL和裂解的半胱天冬酶-3。相比之下，五聚体CRP（pCRP）有诱导细胞AD病理变化的趋势，但未达到统计学意义。另一方面，有趣的是，无论ApoE基因型如何，mCRP均不影响原代小胶质细胞中Iba-1和CD68的表达或原代星形胶质细胞中胶质纤维酸性蛋白的表达，此外，mCRP也不影响这些细胞中白细胞介素（IL）-1α、IL-1β和肿瘤坏死因子α的分泌。
这是第一份证明mCRP以ApoE基因型依赖性模式直接诱导神经元细胞AD发病机制的报告，表明mCRP在慢性炎症期间作为参与AD的ε4相关途径的介质发挥作用。
在急性期及之后，五聚体C反应蛋白（pCRP）可不可逆解离形成游离亚基或单体CRP（mCRP）。mCRP以剂量依赖性方式，按照载脂蛋白E（ApoE）ε4>ε3>ε2的模式增加原代神经元中淀粉样β蛋白的产生。mCRP以剂量和时间依赖性方式，按照ε4>ε3>ε2的模式诱导原代神经元中磷酸化tau蛋白的表达。mCRP在阿尔茨海默病风险的ε4相关途径中起重要的介质作用。
