Defective Neuromuscular Synapses in Mice Lacking Amyloid Precursor Protein (APP) and APP-Like Protein 2

Wang, Pei; Yang, Guang; Mosier, Dennis R.; Chang, Pei‐Yeh; Zaidi, Tahire; Gong, Yan Dao; Zhao, Nan; Dominguez, Bertha; Lee, Kuo Fen; Gan, Wen Biao; Zheng, Hui

doi:10.1523/jneurosci.4660-04.2005

Cited by 249 publications

(236 citation statements)

References 41 publications

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“…The coincident phenotypes of APP and DR6 loss of function observed in retinotectal pruning also extend prior data on the neuromuscular junction, in which overshooting of motor axons was observed in mice lacking DR6 (Nikolaev et al, 2009), a phenotype also reported in mice double mutant for APP and its relative, APLP2 (Wang et al, 2005). Coincident loss-of-function phenotypes have also been observed for dendritic spines in cortical layers 2/3, because loss of either APP or DR6 causes an increase in spine density that is dose dependent for both genes (i.e., loss of one APP or DR6 allele gives a partial phenotype that is increased further when the second allele of the gene is lost; Bittner et al, 2009;Kallop et al, 2014); furthermore, loss of both APP and DR6 (in APP;DR6 double-knock-out mouse) does not increase spine density beyond what is observed in either single mutant alone (Kallop et al, 2014)-a nonadditivity of effects that is again consistent with APP and DR6 functioning in the same pathway.…”

Section: Discussionsupporting

confidence: 85%

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Genetic Analysis Reveals that Amyloid Precursor Protein and Death Receptor 6 Function in the Same Pathway to Control Axonal Pruning Independent of β-Secretase

et al. 2014

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In the developing brain, initial neuronal projections are formed through extensive growth and branching of developing axons, but many branches are later pruned to sculpt the mature pattern of connections. Despite its widespread occurrence, the mechanisms controlling pruning remain incompletely characterized. Based on pharmacological and biochemical analysis in vitro and initial genetic analysis in vivo, prior studies implicated a pathway involving binding of the Amyloid Precursor Protein (APP) to Death Receptor 6 (DR6) and activation of a downstream caspase cascade in axonal pruning. Here, we further test their involvement in pruning in vivo and their mechanism of action through extensive genetic and biochemical analysis. Genetic deletion of DR6 was previously shown to impair pruning of retinal axons in vivo. We show that genetic deletion of APP similarly impairs pruning of retinal axons in vivo and provide evidence that APP and DR6 act cell autonomously and in the same pathway to control pruning. Prior analysis had suggested that ␤-secretase cleavage of APP and binding of an N-terminal fragment of APP to DR6 is required for their actions, but further genetic and biochemical analysis reveals that ␤-secretase activity is not required and that high-affinity binding to DR6 requires a more C-terminal portion of the APP ectodomain. These results provide direct support for the model that APP and DR6 function cell autonomously and in the same pathway to control pruning in vivo and raise the possibility of alternate mechanisms for how APP and DR6 control pruning.

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Section: Discussionsupporting

confidence: 85%

“…Because protection is only partial, there must be additional mechanisms that collaborate with APP to mediate degeneration; one candidate is the close APP relative APLP2, especially because it appears to function redundantly with APP in controlling neuromuscular junction formation (Wang et al, 2005;see Discussion).…”

Section: App Regulates Rgc Axon Pruning In Vivomentioning

confidence: 99%

Genetic Analysis Reveals that Amyloid Precursor Protein and Death Receptor 6 Function in the Same Pathway to Control Axonal Pruning Independent of β-Secretase

et al. 2014

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“…Physiologically, APP and its two paralogues, -amyloid precursor-like protein 1 (APLP1) and 2 (APLP2), play essential roles in brain development and neuromuscular synapse formation, and are necessary for survival during the early postnatal stages in mice [2][3][4]. APP is a receptor-like, type-I membrane protein, which has a large extracellular domain, a transmembrane domain, …”

Section: Introductionmentioning

confidence: 99%

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Taru

Suzuki

2009

JAD

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“…1 APP belongs to a family of conserved type I transmembrane proteins including Apl-1 in Caenorhabditis elegans, 2 Appl in Drosophila, 3 and APP, 4 APP-like protein 1 (APLP1) 5 and APLP2 6,7 in mammals.…”

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confidence: 99%

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

et al. 2006

Cell Death Differ

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Amyloid precursor protein (APP) is a member of a gene family that includes two APP-like proteins, APLP1 and 2. Recently, it has been reported that APLP1 and 2 undergo presenilin-dependent c-secretase cleavage, as does APP, resulting in the release of an B6 kDa intracellular C-terminal domain (ICD), which can translocate into the nucleus. In this study, we demonstrate that the APLP2-ICDs interact with CP2/LSF/LBP1 (CP2) transcription factor in the nucleus and induce the expression of glycogen synthase kinase 3b (GSK-3b), which has broad-ranged substrates such as s-and b-catenin. The significance of this finding is substantiated by the in vivo evidence of the increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2, and for GSK-3b in the AD patients' brain. Taken together, these results suggest that APLP2-ICDs contribute to the AD pathogenesis, by inducing GSK-3b expression through the interaction with CP2 transcription factor in the nucleus. The pathology of Alzheimer's disease (AD) is characterized by the deposition of neuritic plaques, of which the principal components are 40 and 42 amino-acid amyloid beta peptides (Ab) derived from amyloid precursor protein (APP). 1 APP belongs to a family of conserved type I transmembrane proteins including Apl-1 in Caenorhabditis elegans, 2 Appl in Drosophila, 3 and APP, 4 APP-like protein 1 (APLP1) 5 and APLP2 6,7 in mammals.APLP1 and 2 display substantial amino-acid and domain homologies with APP. Although they do not have an Ab domain, their intracellular C-terminal domains (ICDs) are highly similar to that of APP. 8 APLP1 is known to be implicated in synaptogenesis, 9,10 and recombinant APLP2 possesses an ability to promote neurite outgrowth. 11 However, their physiological roles in neurons are still not fully understood. In the brains of AD patients, APLP2 immunoreactivity has been detected in a subset of neuritic plaques, 12 suggesting that APLP2 might be involved in the pathogenesis of AD.APLP2 matures through the same secretory/cleavage pathway as APP 7 and previously, APLP1 and 2 were reported to be processed by g-secretase in a presenilin 1-dependent manner. 8,10 The APLP family can be also cleaved by esecretase to generate the ICD composed of the last 50 amino acids of APLPs C-terminus (C50). 13,14 Moreover, the ICDs of APLP1 and APLP2 produced by g-secretase enhanced Fe65-dependent gene transcriptional activation, as have been reported for the APP intracellular domain (AICD). 10 Fe65, which is known to be ones of the adaptor proteins for APP, contains three protein-protein interaction domains, a WW and two phosphotyrosine binding (PTB) domains. The PTB2 domain, which is located in the C-terminal half of the molecule, is responsible for the interaction between Fe65 and the cytosolic tail of APP through the YENPTY domain of APP. 15 Here, we demonstrate that the ICDs of APLP2 (APLP2-ICDs: C57, C50) interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase 3b (GSK-3b) expression, whereas their point mutants with...

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Defective Neuromuscular Synapses in Mice Lacking Amyloid Precursor Protein (APP) and APP-Like Protein 2

Cited by 249 publications

References 41 publications

Genetic Analysis Reveals that Amyloid Precursor Protein and Death Receptor 6 Function in the Same Pathway to Control Axonal Pruning Independent of β-Secretase

Genetic Analysis Reveals that Amyloid Precursor Protein and Death Receptor 6 Function in the Same Pathway to Control Axonal Pruning Independent of β-Secretase

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

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