Analysis of amyloid precursor protein function in Drosophila melanogaster

Abstract

The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer's Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation.

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

“…Notably, secretase-dependent processing of APPL produces the same types of cleavage fragments as APP 695 (Figure 1A), including soluble ectodomain fragments (sAPPLs), membrane-bound CTFs, intracellular AICD fragments, and a neurotoxic Aβ-like peptide (Luo et al, 1995; Fossgreen et al, 1998; Greeve et al, 2004; Carmine-Simmen et al, 2009; Poeck et al, 2012). To investigate the expression and processing of endogenous APPL in the insect nervous system, we used a panel of antibodies against different domains of Manduca APPL (Swanson et al, 2005; Ramaker et al, 2013).…”

“…In contrast, insects express a single APP ortholog (APP-like, or APPL) that shares all of the canonical features of human APP 695 (the predominant neuronal isoform), including highly conserved extracellular and intracellular domains that interact with similar classes of ligands and signaling proteins (Luo et al, 1990; Torroja et al, 1999; Ashley et al, 2005; Swanson et al, 2005). 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).…”

Role of Drosophila Amyloid Precursor Protein in Memory Formation

“…Indeed, APPL overexpression in old age leads to Thioflavin-S-positive aggregates that are associated with neurodegeneration, suggesting that APPL processing produces an analog of human Aβ (Carmine-Simmen et al, 2009). Importantly, APPL undergoes similar proteolytic pathways to APP (Poeck et al, 2011), and the homologs of all mammalian secretases have been characterized in the fly (Rooke et al, 1996; Boulianne et al, 1997; Hong and Koo, 1997; Carmine-Simmen et al, 2009). …”

Modeling the complex pathology of Alzheimer's disease in Drosophila

“…The Drosophila APP orthologue, APPL, has a 25% identity and a 39% similarity (Luo et al, 1990) and shares the basic structure of human APP (Poeck et al, 2012). Appl deficient flies show mild behavioral phenotypes associated with locomotor reactivity that are partially rescued by human APP , demonstrating the functional conservation of APP (Luo et al, 1992).…”