A novel mouse model for N-terminal truncated A2-x generation through meprin overexpression in astrocytes

Neurotoxic amyloid-beta (A beta) peptides cause neurodegeneration in Alzheimer's disease (AD) patients' brains. They are released upon proteolytic processing of the amyloid precursor protein (APP) extracellularly at the beta-secretase site and intramembranously at the gamma-secretase site. Several AD mouse models were developed to conduct respective research in vivo. Most of these classical models overexpress human APP with mutations driving AD-associated pathogenic APP processing. However, the resulting pattern of A beta species in the mouse brains differs from those observed in AD patients' brains. Particularly mutations proximal to the beta-secretase cleavage site (e.g., the so-called Swedish APP (APPswe) fostering A beta 1-x formation) lead to artificial A beta production, as N-terminally truncated A beta peptides are hardly present in these mouse brains. Meprin beta is an alternative beta-secretase upregulated in brains of AD patients and capable of generating N-terminally truncated A beta 2-x peptides. Therefore, we aimed to generate a mouse model for the production of so far underestimated A beta 2-x peptides by conditionally overexpressing meprin beta in astrocytes. We chose astrocytes as meprin beta was detected in this cell type in close proximity to A beta plaques in AD patients' brains. The meprin beta-overexpressing mice showed elevated amyloidogenic APP processing detected with a newly generated neo-epitope-specific antibody. Furthermore, we observed elevated A beta production from endogenous APP as well as AD-related behavior changes (hyperlocomotion and deficits in spatial memory). The novel mouse model as well as the established tools and methods will be helpful to further characterize APP cleavage and the impact of different A beta species in future studies.