Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain

Leyssen, Maarten; Ayaz, Derya; Hébert, Sébastien S.; Reeve, Simon; Strooper, Bart De; Hassan, Bassem A.

doi:10.1038/sj.emboj.7600757

Cited by 218 publications

(175 citation statements)

References 51 publications

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“…26 APPL overexpression has been shown to induce post-developmental neurite arborization. 36 Similarly, Zhu et al 37 showed the cell-autonomous involvement of Drosophila Cul3 in axonal arborization and dendritic elaboration of mushroom body neurons. The neddylation of cullins is important for their proper functioning, so that the APPL overexpression phenotypes of these reports may be directly related to reduced neddylation.…”

Section: Discussionmentioning

confidence: 96%

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

Kim

et al. 2006

Cell Death Differ

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b-Amyloid precursor protein binding protein 1 (APP-BP1) was previously identified based on its binding to the carboxyl terminal of b-amyloid precursor protein. In this report, we have discovered that a mutation of dAPP-BP1 (Drosophila ortholog of APP-BP1) hinders tissue development, causes apoptosis in imaginal disc cells, and blocks the NEDD8 conjugation pathway. We show that dAPP-BP1 specifically binds the intracellular domain of APP-like protein (APPL). The dAPP-BP1 mutation partially suppresses the abnormal macrochaete phenotype of Appl d , while overexpression of dAPP-BP1 causes abnormal macrochaetes. When APPL is overexpressed, the normal bristle pattern in the fly thorax is disturbed and apoptosis is induced in wing imaginal discs. APPL overexpression phenotypes are enhanced by reducing the level of dAPP-BP1. APPL overexpression is shown to inhibit the NEDD8 conjugation pathway. APPL-induced apoptosis is rescued by overexpression of dAPP-BP1. Our data suggest that APPL and dAPP-BP1 interact antagonistically during Drosophila development.

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Section: Discussionmentioning

confidence: 96%

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

Kim

et al. 2006

Cell Death Differ

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“…Moreover, APP itself is transcriptionally up-regulated in response to nerve transections, trauma, and cerebral ischemia in the nervous system (Banati et al, 1993;Shi et al, 2000;Ciallella et al, 2002), all processes that result in cytoskeletal reorganization. In Drosophila, APP expression is associated with increases in postdevelopmental axonal arborization and loss of neuronal connections, which was strictly linked to the intracellular domain of APP (Leyssen et al, 2005). Moreover, Tg2576 transgenic mice from as early as 4 mo old are positive for rod-like inclusions in the posterior cortex which are composed of actin (Maloney et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Müller

Concannon

Ward

et al. 2007

MBoC

123

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Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of ␤-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD).Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including ␣2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system. INTRODUCTIONThe amyloid precursor protein (APP) is a type-1 transmembrane protein composed of a large extracellular and a small intracellular domain and has been widely implicated in the pathogenesis of Alzheimer's disease (AD). APP can undergo proteolytic cleavage by ␤-and ␥-secretase activities, resulting in the production of ␤-amyloid (A␤) (Selkoe, 1994). A␤ is the main constituent of amyloid plaques and is thought to be neurotoxic by inducing oxidative stress, inflammation, and neurodegeneration (Mattson, 2004). The intraneuronal accumulation of A␤ protofibrils is thought to cause progressive neurotoxicity in cortical neurons (Hartley et al., 1999). In addition, the secretion of soluble A␤ oligomers inhibits hippocampal long-term potentiation and alters the memory of complex learned behavior (Walsh et al., 2005).The APP intracellular domain (AICD), a small 6-kDa protein, originates from APP cleavage mediated by ␥-secretase activity (Octave et al., 2000). This cleavage can occur after Val636 (AICD59), Ala638 (AICD57), or Leu645 (AICD50) corresponding to the ␥-or -cleavage site ( Figure 1A) of the ␥-secretase complex (Sastre et al., 2001;Yu et al., 2001). More recently, AICD was shown to have transactivation potential (Cao and Sudhof, 2001). AICD levels are detectable in membrane fractions of murine total brain homogenates, and they increase significantly in mice overexpressing the Swedish mutation of human APP (Ryan and Pimplikar, 2005). Moreover, Hirano bodies found in the degenerating neurons of Alzheimer's patients stain positive with antisera raised against the cytoplasmic domain of APP (Munoz et al., 1993), suggesting an accumulation of AICD during Alzheimer...

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“…Focusing on specific cell types, changes in axonal outgrowth and arborization were also observed in vivo. Induction of APPL in the lateral neurons, a group of neurons that play a key role in the regulation of circadian rhythms, promoted axonal arborization, as did expression of human APP (Leyssen et al, 2005). Interestingly, in these experiments the C-terminus appeared to be required for the axonal outgrowth.…”

Section: Appl and Neuronal Outgrowthmentioning

confidence: 80%

“…Interestingly, it turned out that APPL function is cell-autonomously required for the development of the β-lobe whereas its function in the α-lobe is non-autonomous. Rescue experiments showed that the C-terminus was required for the axonal outgrowth of the β-lobe (Soldano et al, 2013), as was suggested for the axonal growth of lateral neurons (Leyssen et al, 2005). In both cell types the function was mediated by the Abelson kinase, which binds to the C-terminus of APPL via the adapter protein disabled (Leyssen et al, 2005;Soldano et al, 2013).…”

Section: Appl and Neuronal Outgrowthmentioning

confidence: 90%

Analysis of amyloid precursor protein function in Drosophila melanogaster

2011

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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.

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Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain

Cited by 218 publications

References 51 publications

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Analysis of amyloid precursor protein function in Drosophila melanogaster

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