The Full-Length Form of theDrosophilaAmyloid Precursor Protein Is Involved in Memory Formation

Abstract

The APP plays a central role in AD, a pathology that first manifests as a memory decline. Understanding the role of APP in normal cognition is fundamental in understanding the progression of AD, and mammalian studies have pointed to a role of secreted APP␣ in memory. In Drosophila, we recently showed that APPL, the fly APP ortholog, is required for associative memory. In the present study, we aimed to characterize which form of APPL is involved in this process. We show that expression of a secreted-APPL form in the mushroom bodies, the center for olfactory memory, is able to rescue the memory deficit caused by APPL partial loss of function. We next assessed the impact on memory of the Drosophila ␣-secretase kuzbanian (KUZ), the enzyme initiating the nonamyloidogenic pathway that produces secreted APPL␣. Strikingly, KUZ overexpression not only failed to rescue the memory deficit caused by APPL loss of function, it exacerbated this deficit. We further show that in addition to an increase in secreted-APPL forms, KUZ overexpression caused a decrease of membrane-bound full-length species that could explain the memory deficit. Indeed, we observed that transient expression of a constitutive membrane-bound mutant APPL form is sufficient to rescue the memory deficit caused by APPL reduction, revealing for the first time a role of full-length APPL in memory formation. Our data demonstrate that, in addition to secreted APPL, the noncleaved form is involved in memory, raising the possibility that secreted and full-length APPL act together in memory processes.

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

“…As with other APP family proteins, insect APPL is subject to cleavage by a combination of α, β, and γ-secretases (Figures 1G–J), consistent with the identification of all three secretase classes in multiple insect systems (Luo et al, 1990; Ramabhadran et al, 1993; Fossgreen et al, 1998; Greeve et al, 2004; Groth et al, 2010; Bolkan et al, 2012; Prussing et al, 2013; Pace et al, 2014; Bourdet et al, 2015; Lavore et al, 2015; Zheng et al, 2015). Likewise, our studies showed that Manduca APPL is preferentially cleaved by α-secretases under normal circumstances, as previously reported for both Drosophila APPL and human APP 695 (Haass et al, 2012; Wentzell et al, 2012; Zhang et al, 2012).…”

“…Like APP, APPL is subject to proteolytic processing by α, β, and γ-secretases that generate an analogous spectrum of cleavage fragments, including sAPPs, CTFs, AICDs, and an Aβ-like peptide (Luo et al, 1995; Greeve et al, 2004; Carmine-Simmen et al, 2009; Poeck et al, 2012). Also like mammalian APP, APPL plays important roles in the developing nervous system, participating in the control of neuronal migration and synaptic plasticity (Torroja et al, 1999; Ashley et al, 2005; Ramaker et al, 2013; Soldano et al, 2013; Bourdet et al, 2015). Notably, studies in Drosophila have shown that defects caused by the loss of APPL can be rescued by the expression of human APP 695 (Luo et al, 1992; Wentzell et al, 2012), indicating that these proteins are both structurally and functionally homologous.…”

Role of Drosophila Amyloid Precursor Protein in Memory Formation

“…APPL silencing in the MB of adult flies was shown to disrupt MTM and LTM, but neither learning nor ARM formation was affected (Goguel et al, 2011; Bourdet et al, 2015b). MTM and LTM are two memory phases known to share identical neuronal circuits (Bouzaiane et al, 2015), indicating a role for APPL in these structures.…”

“…Consequently, APPL sd is exclusively expressed as a transmembrane protein. Overexpression of APPL s in the adult MB rescued the MTM deficit caused by a reduction of endogenous APPL levels, indicating that a secreted fragment of APPL is involved in memory (Bourdet et al, 2015b). This is consistent with mammalian studies showing a role for sAPPα in memory (Meziane et al, 1998; Bour et al, 2004; Ring et al, 2007; Taylor et al, 2008).…”

“…This is consistent with mammalian studies showing a role for sAPPα in memory (Meziane et al, 1998; Bour et al, 2004; Ring et al, 2007; Taylor et al, 2008). Unexpectedly, however, overexpression of the fly α-secretase KUZ (Rooke et al, 1996), thought to increase sAPPLα levels, did not rescue the memory deficit caused by APPL partial loss-of-function, and even further exacerbated the MTM impairment (Bourdet et al, 2015b). Interestingly, KUZ overexpression in this context was shown to decrease full-length APPL (fl-APPL) protein levels, prompting the hypothesis that the exacerbation of the memory phenotype resulted from a reduction of fl-APPL levels.…”