The Drosophila Homologue of the Amyloid Precursor Protein Is a Conserved Modulator of Wnt PCP Signaling

Soldano, Alessia; Okray, Zeynep; Janovská, Pavlína; Tmejová, Kateřina; Reynaud, Elodie; Claeys, Annelies; Yan, Jiekun; Atak, Zeynep Kalender; Strooper, Bart De; Dura, Jean-Maurice; Bryja, Vı́tězslav; Hassan, Bassem A.

doi:10.1371/journal.pbio.1001562

Cited by 61 publications

(115 citation statements)

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“…APPL knockout Drosophila are viable but have subtle behavioral defects (including conditional learning defects) (Luo et al, 1992) and defects in maintenance of synaptic boutons at the neuromuscular junction (NMJ) (Torroja et al, 1999b) and are more vulnerable to brain injury (Leyssen et al, 2005). APPL also modulates the Wnt-planar cell polarity (PCP) pathway required for axonal outgrowth during neuronal development (Soldano et al, 2013). Finally, deletion mutations of the Drosophila APPL gene, or animals overexpressing either APPL, human APP, or the C terminus of human APLP2 exhibit Ab-independent defects in axonal transport mediated by the conserved cytoplasmic C terminus (Goldstein, 2012;Gunawardena and Goldstein, 2001;Rusu et al, 2007;Torroja et al, 1999a).…”

Section: Possible Functions Of App Family Members In Brain Developmenmentioning

confidence: 99%

“…APP C99, but not C83, is preferentially phosphorylated on Thr743 (Lee et al, 2003), and Pin1 binds C99 but not full-length APP nor C83, indicating that differential APP cleavage controls specific downstream events (Akiyama et al, 2005). One such event might be signaling through the Wnt-PNP receptor complex (Soldano et al, 2013). C99 interacts with multiple proteins of this complex (Vangl2, Frizzeld, and Frizzeld5) that regulate cellular polarity and axonal outgrowth, but whether this is phospho dependent has not been tested (Soldano et al, 2013).…”

Section: App Proteolytic Products: Unique Proteins With Specialized Fmentioning

confidence: 99%

“…One such event might be signaling through the Wnt-PNP receptor complex (Soldano et al, 2013). C99 interacts with multiple proteins of this complex (Vangl2, Frizzeld, and Frizzeld5) that regulate cellular polarity and axonal outgrowth, but whether this is phospho dependent has not been tested (Soldano et al, 2013). In addition to adaptor and signaling proteins, APP CTFs are also implicated in interactions with motor proteins such as kinesin, myosin, and dynein (Cottrell et al, 2005;Goldstein, 2012), thereby possibly controlling their own transport (Rodrigues et al, 2012).…”

Section: App Proteolytic Products: Unique Proteins With Specialized Fmentioning

confidence: 99%

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Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

2015

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Amyloid precursor protein (APP) is a key player in Alzheimer's disease (AD). The Aβ fragments of APP are the major constituent of AD-associated amyloid plaques, and mutations or duplications of the gene coding for APP can cause familial AD. Here we review the roles of APP in neuronal development, signaling, intracellular transport, and other aspects of neuronal homeostasis. We suggest that APP acts as a signaling nexus that transduces information about a range of extracellular conditions, including neuronal damage, to induction of intracellular signaling events. Subtle disruptions of APP signaling functions may be major contributors to AD-causing neuronal dysfunction.

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Section: Possible Functions Of App Family Members In Brain Developmenmentioning

confidence: 99%

Section: App Proteolytic Products: Unique Proteins With Specialized Fmentioning

confidence: 99%

Section: App Proteolytic Products: Unique Proteins With Specialized Fmentioning

confidence: 99%

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Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

2015

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

Ramaker

Cargill

Swanson

et al. 2016

Front. Mol. Neurosci.

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Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (Aβ) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane glycoproteins expressed by all higher organisms, including two mammalian orthologs (APLP1 and APLP2) that have complicated investigations into the specific activities of APP. By comparison, insects express only a single APP-related protein (APP-Like, or APPL) that contains the same protein interaction domains identified in APP. However, unlike its mammalian orthologs, APPL is only expressed by neurons, greatly simplifying an analysis of its functions in vivo. Like APP, APPL is processed by secretases to generate a similar array of extracellular and intracellular cleavage fragments, as well as an Aβ-like fragment that can induce neurotoxic responses in the brain. Exploiting the complementary advantages of two insect models (Drosophila melanogaster and Manduca sexta), we have investigated the regulation of APPL trafficking and processing with respect to different aspects of neuronal development. By comparing the behavior of endogenously expressed APPL with fluorescently tagged versions of APPL and APP, we have shown that some full-length protein is consistently trafficked into the most motile regions of developing neurons both in vitro and in vivo. Concurrently, much of the holoprotein is rapidly processed into N- and C-terminal fragments that undergo bi-directional transport within distinct vesicle populations. Unexpectedly, we also discovered that APPL can be transiently sequestered into an amphisome-like compartment in developing neurons, while manipulations targeting APPL cleavage altered their motile behavior in cultured embryos. These data suggest that multiple mechanisms restrict the bioavailability of the holoprotein to regulate APPL-dependent responses within the nervous system. Lastly, targeted expression of our double-tagged constructs (combined with time-lapse imaging) revealed that APP family proteins are subject to complex patterns of trafficking and processing that vary dramatically between different neuronal subtypes. In combination, our results provide a new perspective on how the regulation of APP family proteins can be modulated to accommodate a variety of cell type-specific responses within the embryonic and adult nervous system.

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“…melanogaster has been used extensively to study the role of the APP homolog APPL in the context of axonal growth. Recently, it has been shown that Appl null flies (Appl d ) display developmental axonal growth defects in mushroom bodies, which house a neuronal population that is important for learning and memory (Soldano et al, 2013), as well as in retinal axons (Mora et al, 2013). The expression of full-length APPL, but not sAPPL nor a membranetethered form lacking the conserved C-terminus, rescued this phenotype, suggesting that the APPL C-terminus is crucial for its function.…”

Section: The Role Of App In Neurite Outgrowth and Guidancementioning

confidence: 99%

Amyloid precursor protein and neural development

2014

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Interest in the amyloid precursor protein (APP) has increased in recent years due to its involvement in Alzheimer's disease. Since its molecular cloning, significant genetic and biochemical work has focused on the role of APP in the pathogenesis of this disease. Thus far, however, these studies have failed to deliver successful therapies. This suggests that understanding the basic biology of APP and its physiological role during development might be a crucial missing link for a better comprehension of Alzheimer's disease. Here, we present an overview of some of the key studies performed in various model organisms that have revealed roles for APP at different stages of neuronal development.

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The Drosophila Homologue of the Amyloid Precursor Protein Is a Conserved Modulator of Wnt PCP Signaling

Abstract: The Drosophila homolog of the Alzheimer's disease protein APP, known as APPL, regulates axon growth during brain development.

Cited by 61 publications

References 41 publications

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

Amyloid precursor protein and neural development

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