Interactions between amyloid precursor protein-like (APPL) and MAGUK scaffolding proteins contribute to appetitive long-term memory in Drosophila melanogaster

Abstract

Amyloid precursor protein (APP), the precursor of amyloid beta peptide, plays a central role in Alzheimer’s disease (AD), a pathology characterized by memory decline and synaptic loss upon aging. Understanding the physiological role of APP is fundamental in deciphering the progression of AD, and several studies suggest a synaptic function via protein-protein interactions. Nevertheless, it remains unclear whether and how these interactions contribute to memory. In Drosophila, we previously showed that APP-like (APPL), the fly APP homolog, is required for aversive associative memory in the olfactory memory center, the mushroom body (MB). In the present study, we show that APPL is required for appetitive long-term memory (LTM), another form of associative memory, in a specific neuronal subpopulation of the MB, the α′/β′ Kenyon cells. Using a biochemical approach, we identify the synaptic MAGUK (membrane-associated guanylate kinase) proteins X11, CASK, Dlgh2 and Dlgh4 as interactants of the APP intracellular domain (AICD). Next, we show that the Drosophila homologs CASK and Dlg are also required for appetitive LTM in the α′/β′ neurons. Finally, using a double RNAi approach, we demonstrate that genetic interactions between APPL and CASK, as well as between APPL and Dlg, are critical for appetitive LTM. In summary, our results suggest that APPL contributes to associative long-term memory through its interactions with the main synaptic scaffolding proteins CASK and Dlg. This function should be conserved across species.

Keywords:

• Drosophila
• long-term memory
• MAGUK proteins
• Amyloid precursor protein
• mushroom bodies
• CASK
• Dlg

Acknowledgements

The authors thank the TRiP consortium at Harvard Medical School (NIH/NIGMS R01-GM084947) for providing transgenic RNAi fly stocks. The authors thank Aurélie Lampin-Saint-Amaux and Audrey Lombi for assistance with the behavior experiments. The authors are grateful to Dr. N. E. Reist for providing us the anti-Synaptotagmin 1 antibody. The authors thank the Core Facility BioSupraMol of the Freie Universität Berlin for the use of the Leica TCS SP8 system and for support.

Author contributions

Conceptualization: A.P., T.P., B.S., S.J.S., T.W., B.H.; investigation: B.S., C.N., M.M., T.W. and A.P; writing/original draft preparation: B.S. and A.P.; writing/review and editing: A.P., B.S., T.P., M.M., S.J.S, and T.W.; supervision: A.P., T.P., B.H., and S.J.S.; funding acquisition: T.P. and S.J.S.

Disclosure statement

The authors declare no competing financial interests.

Additional information

Funding

T.P. received grant support from the Fondation pour la Recherche Médicale [DEQ20140329540]. B.S. is a recipient of the Graduate Program fellowship from the École des Neurosciences de Paris (ENP).