Functional role of meprin beta in Alzheimer s disease

淀粉样β蛋白(Abeta)的产生被认为在阿尔茨海默病(AD)的发病机制中起重要作用，因此有必要详细破译导致Abeta亚型产生的蛋白分解网络。Aβ多肽是由淀粉样前体蛋白(APP)在淀粉样蛋白形成途径中通过BACE 1(β位点APP裂解酶1)和γ-分泌酶复合体连续两次切割而产生的。由于两种分泌酶都不局限于单一的位点，因此Abeta多肽的长度各不相同。BACE 1可以从p1或p11(Abeta1-x/11-x)位置开始产生Abeta，而γ-分泌酶复合体有几个裂解位点，可以产生不同的Abeta的C末端。最有趣的是，在AD患者中也描述了以p2(Abeta2-x)中的丙氨酸开始的N末端截短的Abeta变体，这不能归因于BACE 1的活性。在第一个资助期间，我们发现meprin beta是APP加工过程中的一种酶，它能够产生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的活性，特别是从APP序列中没有N端家族性AD突变的APP序列中产生。在第二个资助期，我们将主要关注Meprin beta在AD发病中的体内作用。疾病发展的一个方面是Abeta多肽的聚集倾向。最近，我们已经证明了N-末端截短的Abeta2-40多肽增强了其他Abeta物种的聚集特性。我们将使用过度表达APP伦敦突变(APPlon)的小鼠，将其与meprin beta缺陷小鼠和meprin beta转基因小鼠杂交，以分析meprin beta在AD进展中的作用。此外，我们将对APPlon小鼠应用梅普林β的直接病毒诱导，最终促进这些动物的AD病理。这个项目将表明，梅普林β是否直接参与了AD表型的进展。

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.