The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

Hicks, David; Makova, Natalia Z.; Gough, Mallory; Parkin, Edward T.; Nalivaeva, Natalia N.; Turner, Anthony J.

doi:10.1074/jbc.m113.461269

Cited by 20 publications

(20 citation statements)

References 81 publications

(96 reference statements)

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“…An increasing list of AICD candidate genes has emerged from various models (reviewed in Pardossi-Piquard and Checler, 2012). On the other hand, APP was also reported to regulate gene transcription independently of AICD release (Hicks et al, 2013;Pierrot et al, 2013). It is thus so far quite impossible to clearly define (i) the precise identity of APP target genes in neurons (ii) the related molecular pathways underlying APP-dependent gene transcription (iii) how APP target genes relate to APP neuronal function.…”

Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Opsomer¹,

Contino²,

Perrin

et al. 2020

eNeuro

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The Amyloid Precursor Protein (APP) has been extensively studied as the precursor of the βamyloid peptide (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer's disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain. It resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell-cell interaction and/or activation of intracellular signaling pathways. In this respect, the APP intracellular domain (AICD) was reported to act as a transcriptional regulator. Here, we used a transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and upon maturation of primary cortical neurons. Surprisingly, the overall transcriptional changes were subtle, but a more detailed analysis pointed to genes clustered in neuronal-activity dependent pathways. In particular, we observed a decreased transcription of Neuronal PAS domain protein 4 (NPAS4) in APP-/-neurons. NPAS4 is an inducible transcription factor (ITF) regulated by neuronal depolarization. The down-regulation of NPAS4 co-occurs with an increased production of the inhibitory neurotransmitter GABA and a reduced expression of the GABA A receptors alpha1. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Patch-clamp investigation did not reveal any functional decrease of GABA A receptors activity, but LTP measurement supported an increased GABA component in synaptic transmission of APP-/-mice. Together, NPAS4 appears to be a downstream target involved in APP-dependent regulation of inhibitory synaptic transmission.

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Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Opsomer¹,

Contino²,

Perrin

et al. 2020

eNeuro

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show abstract

“…Furthermore, APP-dependent Npas4 expression at DIV7 does not rely on AICD release, although DIV7 corresponds to the differentiation stage where AICD is readily produced by neurons (Kimberly et al, 2005). Previous studies indicated that regulation of some APP target genes does not require the generation of AICD (Hicks et al, 2013). Quite strikingly, DAPT treatments, used to block AICD production in our setup, increased Npas4 expression in APP+/+ neurons.…”

Section: Discussionmentioning

confidence: 99%

“…An increasing list of AICD candidate genes has emerged from various models (reviewed in Pardossi-Piquard and Checler, 2012). Some of these candidate genes failed to be confirmed by transcription analysis in APP-deficient cell lines (Hebert et al, 2006; Waldron et al, 2008), and APP was also reported to regulate gene transcription independently of AICD release (Hicks et al, 2013; Pierrot et al, 2013). It is so far impossible to clearly define (i) the precise identity of APP target genes in neurons (ii) how these APP target genes relate to APP neuronal function (iii) the mechanism involved in APP-dependent in gene transcription.…”

Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Protein (APP) controls excitatory/inhibitory synaptic inputs by regulating the transcriptional activator Neuronal PAS Domain Protein 4 (NPAS4)

Opsomer

Contino

Perrin

et al. 2018

Preprint

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33Sequential proteolysis of the amyloid precursor protein (APP) and amyloid-β peptide (Aβ) release 34is an upstream event in Alzheimer's disease (AD) pathogenesis. The function of APP in neuronal 35 physiology is still, however, poorly understood. Along with its paralog APP-like Proteins 1 and 2 36 (APLP1-2), APP is involved in neurite formation and synaptic function by mechanisms that are 37 not elucidated. APP is a single-pass transmembrane protein expressed at high levels in the brain 38 that resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies 39 on cell interaction processes and/or activation of intracellular pathways of signal transduction. 40Along this line, the APP intracellular domain (AICD) was reported to act as a transcriptional factor 41 for targeted gene activation that mediates physiological APP functions. Here, we used an unbiased 42 transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent 43 embryonic cortex and upon maturation of primary cortical neurons. The transcriptome analysis did 44 not detect any significant differences in expression of previously proposed AICD target genes. The 45 overall transcriptional changes were subtle, but we found that genes clustered in neuronal-activity 46 dependent pathways are dysregulated in the absence of APP. Among these genes, we found the 47 activity-dependent Neuronal PAS domain protein 4 (NPAS4) Immediate Early Gene to be 48 downregulated in the absence of APP. Down-regulation of NPAS4 in APP knock-out (KO) neurons 49is not related to AICD but to the APP ectodomain. We studied the effect of APP deficiency on 50GABAergic and glutamatergic transmission, and found an increased production of the inhibitory 51 neurotransmitter GABA in APP KO neurons, along with a reduced expression of the GABA (A) 52 receptors alpha1, suggesting an impaired GABAergic neurotransmission in the absence of APP. 53 CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Altogether, our 54 results point out a new role for APP in the regulation of excitatory/inhibitory neurotransmission 55 through the regulation of the activity-dependent NPAS4 gene. 56 4 excitation onto the same neurons (Spiegel et al., 2014). NPAS4 is therefore a key player in the 96 maintenance of excitatory/inhibitory balance in neuronal network. 97The precise mechanisms underlying APP synaptic functions are still elusive. One could suspect 98 APP to regulate the expression of genes involved in synaptic activity, or to shape the structure of 99 the synapse. APP was shown to control gene expression through its intracellular domain called 100AICD. An increasing list of AICD candidate genes has emerged from various models (reviewed in 101Pardossi-Piquard and Checler, 2012). Some of these candidate genes failed to be confirmed by 102 transcription analysis in APP-deficient cell lines (Hebert et al., 2006; Waldron et al., 2008), and 103 APP was also reported to regulate gene transcription independently of AICD...

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“…Our data indicate that APP‐dependent GDNF transcription is not relying on AICD by the γ‐secretase and, moreover, that APP751 isoforms lacking the C‐terminal region restore GDNF expression to a same extent than native APP751. GDNF might thus belong to another set of APP target genes, like the acetylcholinesterase gene, which is transcriptionally regulated by APP in an AICD‐independent manner (40). One possible hypothesis is that APP recruits through its ectodomain or transmembrane region partner protein directly involved in signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…region restore GDNF expression to a same extent than native APP751. GDNF might thus belong to another set of APP target genes, like the acetylcholinesterase gene, whichistranscriptionallyregulatedbyAPPinanAICDindependent manner (40). One possible hypothesis is t h a tA P Pr e c r u i t st h r o u g hi t se c t o d o m a i no rt r a n smembrane region partner protein directly involved in signal transduction.…”

Section: Discussionmentioning

confidence: 99%

APP‐dependent glial cell line‐derived neurotrophic factor gene expression drives neuromuscular junction formation

et al. 2015

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Besides its crucial role in the pathogenesis of Alzheimer's disease, the knowledge of amyloid precursor protein (APP) physiologic functions remains surprisingly scarce. Here, we show that APP regulates the transcription of the glial cell line‐derived neurotrophic factor (GDNF). APP‐dependent regulation of GDNF expression affects muscle strength, muscular trophy, and both neuronal and muscular differentiation fundamental for neuromuscular junction (NMJ) maturation in vivo. In a nerve‐muscle coculture model set up to modelize NMJ formation in vitro, silencing of muscular APP induces a 30% decrease in secreted GDNF levels and a 40% decrease in the total number of NMJs together with a significant reduction in the density of acetylcholine vesicles at the presynaptic site and in neuronal maturation. These defects are rescued by GDNF expression in muscle cells in the conditions where muscular APP has been previously silenced. Expression of GDNF in muscles of amyloid precursor protein null mice corrected the aberrant synaptic morphology of NMJs. Our findings highlight for the first time that APP‐dependent GDNF expression drives the process of NMJ formation, providing new insights into the link between APP gene regulatory network and physiologic functions.—Stanga, S., Zanou, N., Audouard, E., Tasiaux, B., Contino, S., Vandermeulen, G., René, F., Loeffler, J.‐P., Clotman, F., Gailly, P., Dewachter, I., Octave, J.‐N., Kienlen‐Campard, P. APP‐dependent glial cell line‐derived neurotrophic factor gene expression drives neuromuscular junction formation. FASEB J. 30, 1696–1711 (2016). http://www.fasebj.org

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The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

Cited by 20 publications

References 81 publications

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release

Amyloid Precursor Protein (APP) controls excitatory/inhibitory synaptic inputs by regulating the transcriptional activator Neuronal PAS Domain Protein 4 (NPAS4)

APP‐dependent glial cell line‐derived neurotrophic factor gene expression drives neuromuscular junction formation

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