APOEε4 对散发性阿尔茨海默病 pTau 交互组的影响

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-05-21 DOI:10.1007/s00401-024-02744-8
Manon Thierry, Jackeline Ponce, Mitchell Martà-Ariza, Manor Askenazi, Arline Faustin, Dominique Leitner, Geoffrey Pires, Evgeny Kanshin, Eleanor Drummond, Beatrix Ueberheide, Thomas Wisniewski
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引用次数: 0

摘要

APOEε4是散发性阿尔茨海默病(AD)的主要遗传风险因素。虽然已知 APOEε4 能促进 Aβ 的病理变化,但最近的数据也支持 APOE 多态性对磷酸化 Tau(pTau)病理变化的影响。为了阐明这些潜在的影响,研究人员采用抗 pTau pS396/pS404 (PHF1) 免疫沉淀 (IP) 和质谱 (MS) 结合的方法,分析了 10 例晚期 AD 病例(n = 5 APOEε3/ε3 和 n = 5 APOEε4/ε4)额叶皮层中不同 APOE 基因型的 pTau 相互作用组。在 21 例晚期 AD 病例(n = 11 APOEε3/ε3 和 n = 10 APOEε4/ε4)的额叶皮层中进行了抗 pTau PHF1 和抗 Aβ 4G8 免疫组化分析,对这种蛋白质组学方法进行了补充。我们的数据集包括在 APOEε3/ε3 组和 APOEε4/ε4 组 IPPHF1 样本中富集的 1130 和 1330 个蛋白质(折叠变化≥1.50,IPPHF1 vs IPIgG ctrl)。我们在 APOEε3/ε3 组和 APOEε4/ε4 组中分别发现了 80 个和 68 个可能与 pTau 相互作用的蛋白质(SAINT 得分≥ 0.80;错误发现率 (FDR) ≤ 5%)。在APOEε3/ε3与APOEε4/ε4病例中,共有47/80个蛋白质被鉴定为更有可能与pTau相互作用。功能富集分析表明,这些蛋白与核质区显著相关,并参与 RNA 处理。与此相反,在APOEε4/ε4与APOEε3/ε3病例中,35/68个蛋白质被鉴定为更有可能与pTau相互作用。它们与突触区明显相关,并参与细胞运输。对额叶皮质中Tau病理特征的分析表明,在APOEε4携带者中,由萎缩轴突和突触组成的斑块相关神经嵴的密度较高。在APOEε4/ε4病例中,脑淀粉样血管病更为常见和严重。我们的研究证实了APOE基因型对pTau-亚细胞位置在AD中的影响。这些结果表明,在APOEε4携带者中,pTau向Aβ受影响的脑区发展具有促进作用,这为确定新的治疗靶点铺平了道路。
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The influence of APOEε4 on the pTau interactome in sporadic Alzheimer’s disease

APOEε4 is the major genetic risk factor for sporadic Alzheimer’s disease (AD). Although APOEε4 is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (fold change ≥ 1.50, IPPHF1 vs IPIgG ctrl). We identified 80 and 68 proteins as probable pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOEε3/ε3 vs APOEε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOEε4/ε4 vs APOEε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOEε4 carriers, paving the way to the identification of new therapeutic targets.

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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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