The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease
The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease
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金属蛋白酶 ADAMTS4 生成 N 截短的 Aβ4âx 物种，并将少突胶质细胞标记为阿尔茨海默病中淀粉样肽的来源
DOI：
10.1007/s00401-018-1929-5
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发表时间：
2019
影响因子：
12.7
通讯作者：
Weggen S
中科院分区：
文献类型：
--
作者：
Walter S;Jumpertz T;Hüttenrauch M;Ogorek I;Gerber H;Storck SE;Zampar S;Dimitrov M;Lehmann S;Lepka K;Berndt C;Wiltfang J;Becker-Pauly C;Beher D;Pietrzik CU;Fraering PC;Wirths O;Weggen S
β淀粉样蛋白（Aβ）在脑内的积聚和聚集是阿尔茨海默病（AD）发病机制中的重要环节。全长Aβ肽（主要是Aβ1-40和Aβ1-42）是通过β和γ分泌酶对淀粉样前体蛋白（APP）的连续蛋白水解裂解产生的。然而，对AD患者尸检脑样本的研究表明，大部分不溶性Aβ肽在N端截短，其中Aβ4-x肽尤其丰富。Aβ4-x肽具有高度聚集倾向，但其来源和参与其生成的任何蛋白酶尚不清楚。我们已经在Aβ肽序列中确定了分泌型金属蛋白酶ADAMTS 4（一种具有血小板反应蛋白基序4的去整合素和金属蛋白酶）的识别位点，该位点有助于Aβ4-x肽的生成。HEK 293细胞中ADAMTS 4的诱导性过表达导致Aβ4-40的分泌，但Aβ1-x肽的水平不变。在淀粉样变性的5xFAD小鼠模型中，Aβ4-x肽不仅存在于淀粉样蛋白斑块核心和血管壁中，而且存在于与轴突APP共定位的白色物质结构中。在ADAMTS 4-/-敲除背景下，Aβ4-40水平降低，证实了ADAMTS 4在体内的关键作用。令人惊讶的是，在成年小鼠脑中，ADAMTS 4仅在少突胶质细胞中表达。培养的少突胶质细胞分泌多种Aβ物质，但在ADAMTS 4 −/−小鼠培养物中不存在Aβ4-40肽，表明该酶对该细胞类型中Aβ4-x的产生至关重要。这些发现确立了Aβ4-x肽生成的酶促机制。他们进一步确定少突胶质细胞是这些高度淀粉样蛋白Aβ肽的来源。
Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer’s disease (AD). Full-length Aβ peptides (mainly Aβ1–40 and Aβ1–42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4–x peptides being particularly abundant. Aβ4–x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4–x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4–40 but unchanged levels of Aβ1–x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4–x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4−/−knockout background, Aβ4–40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4–40 peptides were absent in cultures derived from ADAMTS4−/−mice indicating that the enzyme was essential for Aβ4–x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4–x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides.
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影响因子：
6
作者：
Desai, Maya K.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.
影响因子：
7.1
作者：
Reinert J;Richard BC;Klafki HW;Friedrich B;Bayer TA;Wiltfang J;Kovacs GG;Ingelsson M;Lannfelt L;Paetau A;Bergquist J;Wirths O
通讯作者：
Wirths O
DOI：
10.1186/s13195-017-0309-z
发表时间：
2017-10-04
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Wirths O;Walter S;Kraus I;Klafki HW;Stazi M;Oberstein TJ;Ghiso J;Wiltfang J;Bayer TA;Weggen S
通讯作者：
Weggen S
DOI：
10.1083/jcb.200201123
发表时间：
2002-08-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kaether C;Lammich S;Edbauer D;Ertl M;Rietdorf J;Capell A;Steiner H;Haass C
通讯作者：
Haass C
影响因子：
7.1
作者：
Antonios G;Saiepour N;Bouter Y;Richard BC;Paetau A;Verkkoniemi-Ahola A;Lannfelt L;Ingelsson M;Kovacs GG;Pillot T;Wirths O;Bayer TA
通讯作者：
Bayer TA