Drosophila Neprilysin 1 Rescues Memory Deficits Caused by Amyloid-β Peptide

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