日本語
 
Help Privacy Policy ポリシー/免責事項
  詳細検索ブラウズ

アイテム詳細

登録内容を編集ファイル形式で保存
一時保存へ追加
  タグ情報を表示リリース履歴を表示詳細要約

公開
学術論文

Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains

MPS-Authors
/persons/resource/persons182214

Jahn,  Olaf
Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

External Resource
There are no locators available
Fulltext (restricted access)
There are currently no full texts shared for your IP range.
フルテキスト (公開)

Publisher Version
(出版社版), 11MB

付随資料 (公開)
There is no public supplementary material available
引用

Wirths, O., Lehnen, C., Fricke, M., Talucci, I., Klafki, H.-W., Morgado, B., Lehmann, S., Münch, C., Liepold, T., Wiltfang, J., Rostagno, A., Ghiso, J., Maric, H. M., Jahn, O., & Weggen, S. (2024). Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains. Neuropathology and Applied Neurobiology, 50(3):. doi:10.1111/nan.12991.


引用: https://hdl.handle.net/21.11116/0000-000F-7794-4
要旨
Aims:
The aggregation and deposition of amyloid-β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full-length Aβ peptides starting with an aspartate residue in position 1, both N-terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N-terminally truncated Aβ4–x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N-terminally elongated Aβ peptides.

Methods:
We used cell-free and cell-based assays in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N-terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples.

Results:
In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N-terminal to Asp-(1) in the Aβ peptide sequence between residues Glu-(-7) and Ile-(-6) as well as Glu-(-4) and Val-(-3), resulting in the release of N-terminally elongated Aβ-6-x and Aβ-3-x peptides, of which the latter serve as a component in a promising Aβ-based plasma biomarker. Aβ-6/-3-40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ-6/-3-x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N-terminally elongated Aβ-6/-3-x peptides.

Discussion:
The current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD.