齐齐哈尔市第一医院
黑龙江省卫生健康委科研课题（ZYW2021-561）
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目的:基于血清中Tau蛋白磷酸化探讨多奈哌齐对阿尔茨海默(AD)疾病的保护机制。方法:2019年1月到2022年7月,从本院脑病科招募了两组参与者的样本。在第一组样本中包括了58名轻度至重度AD患者和20名健康老年对照组,另一组样本包括37名轻度至中度疑似AD患者的样本,其中18名患者接受了24周多奈哌齐治疗和19名患者接受了24周安慰剂治疗。从患者的血液标本中提取神经元衍生的细胞外囊泡(extracellular vesicles,EVs),并采用ELISA试剂盒对Aβ42、P-T181-tau、P-S396-tau、t-tau、NRGN水平进行分析。结果:与对照组相比,AD患者的EVs中Aβ42、t-tau、P-T181-tau、P-S396-tau水平显著升高(P<0.05),和NRGN水平显著降低(P<0.05)。在AD患者中,t-tau、NRGN和REST的EVs水平与MMSE(t-tau:r =-0.267,P < 0.01；NRGN:r =–0.262,P < 0.01；REST:r =–0.194,P < 0.05)和ADCS-ADL评分(t-tau:r =–0.226,P < 0.05；NRGN:r =–0.257,P < 0.01；REST:r =–0.269,P < 0.01)呈负相关,并与ADAS-cog+评分呈正相关(t-tau:r = 0.237,P < 0.05；NRGN:r = 0.293,P < 0.01；REST:r = 0.225,P < 0.05)。与安慰剂组相比,多奈哌齐组诱导EVs的Aβ42、t-tau、P-T181-tau和P-S396-tau水平从基线到第24周显著降低(P < 0.05)。结论:轻中度AD患者血浆EVs中Aβ42、t-tau、P-T181-tau和P-S393-tau水平升高,并且EVs中t-tau、NRGN和REST的增加与认知和功能下降相关。此外,多奈哌齐治疗诱导轻中度AD患者t-tau、P-T181-tau和P-S396-tau的血浆EVs水平降低。
Objective To explore the protective mechanism of donepezil on Alzheimer"s disease based on Tau protein phosphorylation in serum. Methods From January 2019 to July 2022, samples of two groups of participants were recruited from the Department of Encephalopathy of our hospital. In the first group, 58 patients with mild to severe AD and 20 healthy elderly controls were included, while in the other group, 37 patients with mild to moderate suspected AD were included, of which 18 patients received donepezil treatment for 24 weeks and 19 patients received placebo treatment for 24 weeks. Extracellular vesicles (EVs) derived from neurons were extracted from patients" blood samples, and the levels of Aβ42, P-T181-tau, P-S396-tau, t-tau and NRGN were analyzed by ELISA kit. Results Compared with the control group, the levels of Aβ42, t-tau, P-T181-tau and P-S396-tau in EVs of AD patients increased significantly (P<0.05), and the level of NRGN decreased significantly (P<0.05). In AD patients, the EVs levels of t-tau, NRGN and REST were compared with MMSE (T-Tau: r =-0.267, P < 0.01; NRGN:r =–0.262, P < 0.01; Rest: r =-0.194, P < 0.05) and ADCS-ADL score (t-tau: r =-0.226, P < 0.05; NRGN: r =–0.257, P < 0.01; Rest: r =-0.269, P < 0.01) was negatively correlated with ADAS-cog+ score (t-tau: r = 0.237, P < 0.05; NRGN: r = 0.293, P < 0.01; REST: r = 0.225, P < 0.05). Compared with the placebo group, the levels of Aβ42, t-tau, P-T181-tau and P-S396-tau in donepezil group induced EVs decreased significantly from baseline to the 24th week (P < 0.05). Conclusions The levels of Aβ42, t-tau, P-T181-tau and P-S393-tau in plasma EVs of patients with mild to moderate AD are increased, and the increase of t-tau, NRGN and REST in EVs is related to cognitive and functional decline. In addition, donepezil treatment induced the decrease of plasma EVs levels of t-tau, P-T181-tau and P-S396-tau in patients with mild to moderate AD.
