For over a century, aggregated forms of amyloid-beta protein (A beta) have been viewed as a key hallmark of brains affected by Alzheimer's disease (AD). Today, it remains unknown whether A beta aggregates (oligomers, fibrils or plaques) originate from increased production or decreased catabolism of A beta. Neprilysin (NEP, neutral endopeptidase) is a ubiquitously distributed peptidase, known to degrade A beta, amongst other peptides. In this study, we identified differences in NEP-mediated catabolism of murine and human forms of A beta, using recombinant human NEP, membrane-bound NEP from cells overexpressing the murine peptidase or from human organ preparations with high NEP activity, and purified soluble bovine NEP. NEP degraded murine A beta (mA beta) faster than human A beta (hA beta). These findings were observed with full-length A beta containing 40 or 42 amino acids (A beta(1-40) and A beta(1-42)) and a truncated form (A beta(4-15)), which (i) contains one of the main NEP cleavage sites for A beta (between positions 9 and 10), (ii) harbours all three amino acid differences between murine and human A beta sequences, and (iii) is less prone to aggregation and thus might be a simpler model to investigate A beta biochemistry. While it has previously been shown that mA beta has a far lower propensity to aggregate than hA beta, evidence from this study suggests that a faster NEP-mediated turnover of mA beta may provide additional protection against A beta aggregation in murine species.