Functional role of meprin beta in Alzheimer s disease

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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.