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淀粉样前体蛋白可增加人海马区高斑块负荷的早幼粒细胞白血病核体融合。

Amyloid precursor protein elevates fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load.

机构信息

Department of Molecular Biochemistry, Cell Signalling, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Bochum, Germany.

Leibniz Institute On Aging Research, Jena, Germany.

出版信息

Acta Neuropathol Commun. 2021 Apr 13;9(1):66. doi: 10.1186/s40478-021-01174-x.

DOI:10.1186/s40478-021-01174-x
PMID:33849647
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8042982/
Abstract

The amyloid precursor protein (APP) is a type I transmembrane protein with unknown physiological function but potential impact in neurodegeneration. The current study demonstrates that APP signals to the nucleus causing the generation of aggregates consisting of its adapter protein FE65, the histone acetyltransferase TIP60 and the tumour suppressor proteins p53 and PML. APP C-terminal (APP-CT50) complexes co-localize and co-precipitate with p53 and PML. The PML nuclear body generation is induced and fusion occurs over time depending on APP signalling and STED imaging revealed active gene expression within the complex. We further show that the nuclear aggregates of APP-CT50 fragments together with PML and FE65 are present in the aged human brain but not in cerebral organoids differentiated from iPS cells. Notably, human Alzheimer's disease brains reveal a highly significant reduction of these nuclear aggregates in areas with high plaque load compared to plaque-free areas of the same individual. Based on these results we conclude that APP-CT50 signalling to the nucleus takes place in the aged human brain and is involved in the pathophysiology of AD.

摘要

淀粉样前体蛋白（APP）是一种 I 型跨膜蛋白，其生理功能未知，但可能对神经退行性疾病有影响。本研究表明，APP 向细胞核发出信号，导致其衔接蛋白 FE65、组蛋白乙酰转移酶 TIP60 以及肿瘤抑制蛋白 p53 和 PML 生成聚集物。APP C 端（APP-CT50）复合物与 p53 和 PML 共定位和共沉淀。随着时间的推移，取决于 APP 信号，PML 核体生成被诱导并发生融合，并且在复合物内进行活跃的基因表达。我们进一步表明，APP-CT50 片段与 PML 和 FE65 的核聚集物存在于老年人大脑中，但不存在于从 iPS 细胞分化而来的大脑类器官中。值得注意的是，与同一患者的无斑块区域相比，人类阿尔茨海默病大脑中这些核聚集物在斑块负荷高的区域显著减少。基于这些结果，我们得出结论，APP-CT50 向细胞核的信号转导发生在老年人大脑中，并参与 AD 的病理生理学。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/fd188c3eb543/40478_2021_1174_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/9cbd5eb8ca12/40478_2021_1174_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/6f8f32bd8cd8/40478_2021_1174_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/e37564428dbe/40478_2021_1174_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/00a45fbe0f7b/40478_2021_1174_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/fd188c3eb543/40478_2021_1174_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/9cbd5eb8ca12/40478_2021_1174_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/6f8f32bd8cd8/40478_2021_1174_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/e37564428dbe/40478_2021_1174_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/00a45fbe0f7b/40478_2021_1174_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3257/8042982/fd188c3eb543/40478_2021_1174_Fig5_HTML.jpg

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本文引用的文献

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Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer's disease.小事至关重要：淀粉样前体蛋白细胞内结构域AICD核信号传导在阿尔茨海默病进展和发病机制中的意义
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The functional roles of PML nuclear bodies in genome maintenance.
PML核体在基因组维持中的功能作用。
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Emerging Role of PML Nuclear Bodies in Innate Immune Signaling.早幼粒细胞白血病核体在天然免疫信号传导中的新作用
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