Interactions between amyloid precursor protein-like (APPL) and MAGUK scaffolding proteins contribute to appetitive long-term memory inDrosophila 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 a'/b' 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 a'/b' 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.

Circuit reorganization in the Drosophila mushroom body calyx accompanies memory consolidation

“…The cellular mechanisms leading to the increased number of odorspecific complex MGs remain to be clarified, but they will require a tight coordination between pre-and postsynaptic partners. In this context, mutations in synaptic proteins or in proteins mediating cell-cell interactions, which specifically block LTM, will be of great interest (Silva et al, 2020, Gouzi et al, 2018. We suggest that remodeling could be driven by intrinsic reactivation of KCs during the consolidation phase (Ichinose et al, 2015, Cognigni et al, 2018 or by modulatory inputs into the calyx (Mao and Report ll OPEN ACCESS , Chen et al, 2012, Aso et al, 2014, Busch et al, 2009, Boto et al, 2019.…”

Glia fuel neurons with locally synthesized ketone bodies to sustain memory under starvation

“…The starvation procedure is similar to our previously used procedure before appetitive memory conditioning 62 , 63 . To achieve RNAi induction in the starved condition, 1- to 2-day-old flies were kept at 30 °C for 2 d until conditioning; then, 16 h before conditioning, the flies were transferred to starvation bottles containing only a filter paper soaked with 6.8 ml of mineral water (Evian).…”

Integration of Imaging Genomics Data for the Study of Alzheimer's Disease Using Joint-Connectivity-Based Sparse Nonnegative Matrix Factorization

“…The unregulated expression of PPP2R2C may be related to the onset of AD [42]. The amyloid precursor protein (APP) plays a central role in AD, and CASK is an interactor of the APP intracellular domain (AICD) [43]. [44] has confirmed that in the mouse model of tauopathy, PCSK2 is up-regulated as a differential gene in its hippocampus.…”