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

Opsomer, Reinier-Jacques; Contino, Sabrina; Perrin, Florian; Gualdani, Roberta; Tasiaux, Bernadette; Doyen, Pierre J.; Vergouts, Maxime; Vrancx, Céline; Doshina, Anna; Pierrot, Nathalie; Octave, Jean‐Noël; Gailly, Philippe; Stanga, Serena; Kienlen‐Campard, Pascal

doi:10.1523/eneuro.0322-19.2020

Cited by 27 publications

(27 citation statements)

References 78 publications

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“…Npas4 knockdown can mimics the effects of amyloid precursor protein (APP) deficiency on GAD65 activity and GABA levels. This finding suggests that Npas4 could be a critical signaling factor in APP-dependent inhibitory synaptic transmission and further implicates dysregulation of excitatoryinhibitory balance in AD pathogenesis (Opsomer et al, 2020).…”

Section: Neuroprotective Functions Of Npas4mentioning

confidence: 82%

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

Guo

Zhen

et al. 2020

Front. Neurosci.

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Signaling from the synapse to nucleus is mediated by the integration and propagation of both membrane potential changes (postsynaptic potentials) and intracellular second messenger cascades. The electrical propagation of postsynaptic potentials allows for rapid neural information processing, while propagating second messenger pathways link synaptic activity to the transcription of genes required for neuronal survival and adaptive changes (plasticity) underlying circuit formation and learning. The propagation of activity-induced calcium signals to the cell nucleus is a major synapse-to-nucleus communication pathway. Neuronal PAS domain protein 4 (Npas4) is a recently discovered calcium-dependent transcription factor that regulates the activation of genes involved in the homeostatic regulation of excitatory–inhibitory balance, which is critical for neural circuit formation, function, and ongoing plasticity, as well as for defense against diseases such as epilepsy. Here, we summarize recent findings on the neuroprotective functions of Npas4 and the potential of Npas4 as a therapeutic target for the treatment of acute and chronic diseases of the central nervous system.

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Section: Neuroprotective Functions Of Npas4mentioning

confidence: 82%

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

Guo

Zhen

et al. 2020

Front. Neurosci.

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“…Furthermore, overexpression of APP in diploid fibroblasts and HepG2 cells also resulted in a decrease in FCGRT and FcRn expression ( Figure 4D and E). It is known that APP plays many roles and a growing amount of evidence suggests that APP may also act as a transcriptional regulator [50][51][52] . Cleavage of APP-βCTF by γ-secretase results in the generation of Amyloid-β (Aβ) and APP intracellular domain (AICD) 53 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of the intracellular traffic of IgG in the context of Down syndrome (trisomy 21)

Cejas

Tamaño‐Blanco

Blanco

2020

Preprint

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Persons with Down syndrome (DS, trisomy 21) have widespread cellular protein trafficking defects. There is a paucity of data describing the intracellular transport of IgG in the context of endosomal-lysosomal alterations linked to trisomy 21. In this study, we analyzed the intracellular traffic of IgG mediated by the human neonatal Fc receptor (FcRn) in fibroblast cell lines with trisomy 21. Intracellular IgG trafficking studies in live cells showed that fibroblasts with trisomy 21 exhibit higher proportion of IgG in lysosomes (~10% increase), decreased IgG content in intracellular vesicles (~9% decrease), and a trend towards decreased IgG recycling (~55% decrease) in comparison to diploid cells. Amyloid-beta precursor protein (APP) overexpression in diploid fibroblasts replicated the increase in IgG sorting to the degradative pathway observed in cells with trisomy 21. The impact of APP on the expression of FCGRT (alpha chain component of FcRn) was investigated by APP knock down and overexpression of the APP protein. APP knock down increased the expression of FCGRT mRNA by ~60% in both diploid and trisomic cells. Overexpression of APP in diploid fibroblasts and HepG2 cells resulted in a decrease in FCGRT and FcRn expression. Our results indicate that the intracellular traffic of IgG is altered in cells with trisomy 21. This study lays the foundation for future investigations into the role of FcRn in the context of DS.

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“…Primary cultures of neurons were performed as previously described (Opsomer et al, 2020) on E17 mouse embryos. By dissection, cortices and hippocampi were isolated on ice cold HBSS (Thermo Fisher Scientific, Waltham, USA) and meninges were removed.…”

Section: Methodsmentioning

confidence: 99%

Presenilin-deficient neurons and astrocytes display normal mitochondrial phenotypes

Contino¹,

Vrancx²,

Suelves³

et al. 2020

Preprint

Self Cite

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Presenilins 1 and 2 (PS1 and PS2) are predominantly known as the catalytic subunits of the γ-secretase complex which generates the amyloid-β (Aβ) peptide, the major constituent of the senile plaques found in the brain of Alzheimer’s disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. They are involved in synaptic transmission, endo-lysosomal function and calcium homeostasis. PSs were also found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between the ER and mitochondria by controlling the formation of functional MAMs through its interaction with the Mitofusin2 protein. We have previously demonstrated that the absence of PS2 (PS2KO) alters mitochondrial morphology and function. Indeed, a PS2KO cell line showed reduced mitochondrial respiration along with disrupted mitochondrial cristae and increased glycolysis. This phenotype is restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized Mouse Embryonic Fibroblasts (MEF) and one bottom-line question is to know whether these observations hold true for the Central Nervous System (CNS) cells, and in particular neurons and astrocytes. To that end, we carried out primary PS1KO, PS2KO and PS1/PS2KO (PSdKO) neuronal and astrocyte cultures. All the conditions were obtained in the same litter by crossing PS2 heterozygous and PS1 floxed (PS2+/−; PS1flox/flox) animals. Indeed, contrary to PS2KO mice, PS1KO are not viable and therefore require the use of the Cre-LoxP system to achieve gene deletion in vitro. Strikingly, we did not observe any mitochondrial phenotype in PS1KO, PS2KO or PSdKO primary cultures. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+/NADH ratio. We further investigated the discrepancies between these results and the ones previously reported in the MEF PS2KO cell line by analyzing PS2KO primary fibroblasts. No mitochondrial dysfunction was observed in this model, in line with observations in PS2KO primary neurons and astrocytes. These results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might be the consequence of a cell immortalization process and, therefore, should be critically reconsidered regarding its relevance to AD.

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

Cited by 27 publications

References 78 publications

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

Analysis of the intracellular traffic of IgG in the context of Down syndrome (trisomy 21)

Presenilin-deficient neurons and astrocytes display normal mitochondrial phenotypes

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