Functional role of meprin beta in Alzheimer s disease

meprin beta 在阿尔茨海默病中的功能作用

• 批准号: 236873051
• 负责人: Professor Dr. Christoph Becker-Pauly
• 金额: --
• 依托单位: Institut für Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236873051?language=en
• 关键词: Functional; role; meprin; beta; Alzheimer

The generation of the amyloid beta peptide (Abeta) is hypothesized to play a major role in Alzheimer's disease (AD) pathogenesis, therefore it is essential to decipher the proteolytic network in detail that is responsible for the generation of Abeta isoforms. Abeta peptides are generated from the amyloid precursor protein (APP) in the amyloidogenic pathway through two consecutive cleavage events by BACE 1 (beta-site APP cleaving enzyme 1) and the gamma-secretase complex. As both secretases are not restricted to a single site, Abeta peptides vary in length. BACE 1 can generate Abeta starting in position p1 or p11 (Abeta1-x/11-x) whereas gamma-secretase complex has several cleavage sites and can generate varying C-termini of Abeta. Most interestingly, N-terminal truncated Abeta variants starting with the alanine in p2 (Abeta2-x), which cannot be attributed to BACE 1 activity, have also been described in AD patients. During the first funding period we identified meprin beta as an enzyme in APP processing which is capable to generate N-terminal truncated peptides starting with aspartate in p1 and with alanine in p2 independent of BACE 1 activity specifically from APP sequences which do not harbor an N-terminal familial AD mutation in its sequence. In the second funding period, we will predominantly focus on the in vivo role of meprin beta for the onset of AD. One aspect of disease development is the aggregation propensity of the Abeta-peptides. Recently we have demonstrated that N-terminally truncated Abeta2-40 peptides enhance the aggregation properties of other Abeta species. We will use mice overexpressing an APP London mutation (APPlon), which will be crossed with meprin beta deficient mice and meprin beta transgenic mice to analyze the role of meprin beta on AD progression. Additionally we will apply a direct viral induction of meprin beta to APPlon mice to eventually boost AD pathology in these animals. This project will show, whether meprin beta is directly involved in the progression of an AD phenotype.

淀粉样蛋白β肽（Abeta）的产生被认为在阿尔茨海默病（AD）的发病机制中起主要作用，因此，详细解读负责Abeta异构体产生的蛋白水解网络是至关重要的。在淀粉样蛋白生成途径中，通过BACE 1（β位点APP裂解酶1）和γ-分泌酶复合物的两个连续裂解事件，由淀粉样前体蛋白（APP）生成A β肽。由于两种分泌酶都不限于单一位点，因此Abeta肽的长度不同。BACE 1可以产生从位置p1或p11开始的A β（A β 1-x/11-x），而γ-分泌酶复合物具有几个切割位点，可以产生不同的A β C末端。最有趣的是，在AD患者中也描述了以p2中的丙氨酸（Abeta 2-x）开始的N-末端截短的Abeta变体，其不能归因于BACE 1活性。在第一个资助期内，我们将meprin β鉴定为APP加工中的酶，其能够产生N-末端截短肽，起始于p1中的天冬氨酸和p2中的丙氨酸，而不依赖于BACE 1活性，特别是来自其序列中不含有N-末端家族性AD突变的APP序列。在第二个资助期，我们将主要关注meprin β在AD发病中的体内作用。疾病发展的一个方面是A β-肽的聚集倾向。最近，我们已经证明，N-末端截短的A β 2 -40肽增强了其他A β种类的聚集特性。我们将使用过表达APP伦敦突变（APPlon）的小鼠，将其与meprin β缺陷小鼠和meprin β转基因小鼠杂交，以分析meprin β在AD进展中的作用。此外，我们将对APPlon小鼠应用直接病毒诱导的meprin β，以最终促进这些动物的AD病理学。该项目将显示，是否meprin β直接参与AD表型的进展。

项目成果

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

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
• 发表时间: 2019
• 期刊: Acta Neuropathologica
• 影响因子: 12.7
• 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
• 通讯作者: Weggen S

Degradome of soluble ADAM10 and ADAM17 metalloproteases

• DOI: 10.1007/s00018-019-03184-4
• 发表时间: 2020-01-01
• 期刊: CELLULAR AND MOLECULAR LIFE SCIENCES
• 影响因子: 8
• 作者: Scharfenberg, Franka;Helbig, Andreas;Becker-Pauly, Christoph
• 通讯作者: Becker-Pauly, Christoph