Neprilysins are type-II metalloproteinases known to degrade and inactivate a number of small 46 peptides, in particular the mammalian amyloid-β peptide (Aβ). In Drosophila, several 47 neprilysins expressed in the brain are required for middle-term (MTM) and long-term 48 memory (LTM) in the dorsal paired medial (DPM) neurons, a pair of large neurons that 49 broadly innervate the mushroom bodies (MB), the center of olfactory memory. These data 50 indicate that one or several peptides need to be degraded for MTM and LTM. We have 51 previously shown that the fly amyloid precursor protein (APPL) is required for memory in the 52 MB. We show here that APPL is also required in adult DPM neurons for MTM and LTM 53 formation. This finding prompted us to search for an interaction between neprilysins and 54 Drosophila Aβ (dAβ), a cleavage product of APPL. To find out whether dAβ was a 55 neprilysin’s target, we used inducible drivers to modulate neprilysin 1 (Nep1) and dAβ 56 expression in adult DPM neurons. Experiments were conducted either in both sexes or in 57 females. We show that Nep1 inhibition makes dAβ expression detrimental to both MTM and 58 LTM. Conversely, memory deficits displayed by dAβ-expressing flies are rescued by Nep1 59 overexpression. Consistent with behavioral data, biochemical analyses confirmed that Nep1 60 degrades dAβ. Taken together, our findings establish that Nep1 and dAβ expressed in DPM 61 neurons are functionally linked for memory processes, suggesting that dAβ is a physiological 62 target for Nep1