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Home All issues Volume 31 (2024) OCL, 31 (2024) 1 Full HTML
Open Access
Review
Issue
OCL
Volume 31, 2024
Article Number 1
Number of page(s) 7
Section Nutrition - Health
DOI https://doi.org/10.1051/ocl/2023030
Published online 09 January 2024

© D. Majou and A.-L. Dermenghem, Published by EDP Sciences, 2024

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Highlight

  • DHA, preferential agonist ligand of the PPARα-RXRα and PPARɣ-RXRα heterodimers, is involved in the critical regulation of BDNF activation

  • DHA plays an important role in the gene expression of CREB and CPE, and is involved in the regulation and expression of tPA, as well as the inhibition of PAI-1

1 Introduction

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found in the brain and periphery. This protein, which is encoded by the BDNF gene, helps to support the survival of existing neurons, and it encourages the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. It plays an important role in the activity-dependent regulation of synaptic structure and function, particularly in glutamatergic synapses. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain − areas that are vital to learning, memory, and higher cognition. It stands out due to its high level of expression. Data demonstrate the ability of BDNF to stimulate glucose utilization in response to increased energy demand (Burkhalter and al., 2003) by increasing the expression of the neuronal glucose transporters GLUTs (Arora et al., 2020); this GLUT mRNA expression is dependent on the concentration of BDNF (Burkhalter and al., 2003). BDNF upregulates the expression of neuronal NO synthase (nNOS) and increases the production of NO (Biojone et al., 2015; Kolarow et al., 2014; Xiong et al., 1999). It should be noted that low levels of BDNF coincide with impaired glucose metabolism. BDNF has specific and dose-response protective effects on neuronal toxicity induced by amyloid-β 42 (Arancibia et al., 2008). Decreased BDNF levels are a pathogenic factor involved in Alzheimer’s disease and depression, but also in type 2 diabetes (Krabbe et al., 2007). Several studies have shown the impaired synaptic plasticity of glutamatergic synapses in people suffering from diseases where compromised BDNF function has been observed, such as Huntington’s disease, schizophrenia, depression, anxiety, bipolar disorder etc. (Carvalho et al., 2008).

We have already detailed the mechanisms by which the PI3K/Akt signaling pathway is involved in the efficiency of glucose uptake by stimulating GLUT-1 action and NO-mediated vasodilation (Majou, 2018). We will now clarify how the activation of BDNF supports free estradiol and free insulin-like growth factor-1 (IGF-1) in stimulating the IRS-1/PI3K/Akt signaling pathway and upregulates NMDA receptor activity. Then we will show the major role of DHA in the concentration-dependent stimulatory action of BDNF.

2 The mechanisms of BDNF’s action

Like IGF-1, BDNF is a trophic factor required for the viability and normal function of various neuronal cells. The biological actions of BDNF are mediated by a high-affinity receptor, tyrosine kinase B (TrkB). The binding of IGF-1 to the IGF-1R and of BDNF to TrkB cause a conformational change to these receptors, inducing the autophosphorylation of their tyrosine residues (Hubbard et al., 2000; Revest et al., 2014). These two receptors in turn phosphorylate various intracellular substrates, such as IRS-1 and Shc in the PI3K/Akt signaling pathway. IGF-1 rapidly stimulates the tyrosine phosphorylation of IRS-1 and its association with PI3K; however, its effect on the tyrosine phosphorylation of Shc is weak. Conversely, BDNF differentially upregulates the protein levels of the NR1, NR2A and NR2B NMDA receptor subunits, by a mechanism that is sensitive to transcription and translation inhibitors, and their delivery to the plasma membrane. BDNF thereby upregulates NMDA receptor activity in neurons and increases the potential for calcium influx (Caldeira et al., 2007). Moreover, BDNF induces a rapid surface translocation of AMPA receptors (Narisawa-Saito et al., 2002; Fig. 1).

High-frequency activation of glutamatergic synapses triggers the release of BDNF. This release depends on the activation of postsynaptic ionotropic glutamate receptors and on postsynaptic Ca2+ influx (Hartmann et al., 2021). An increase in synaptic activity and intracellular calcium induces the expression of the BDNF gene (Finkbeiner, 2000). Furthermore, it has been suggested that DHA upregulates BDNF because a DHA deficiency reduces BDNF expression in the frontal cortex, cyclic AMP response element binding protein (CREB) transcription factor activity and mitogen-activated protein kinase (MAPK) activity (Rao et al., 2007); the opposite has been shown in rats with a DHA-enriched diet (Wu et al., 2008), and a high-DHA maternal diet increases the mRNA expression of BDNF, TrkB and CREB, as well as the protein concentration of pCREB in the fetal-brain as gestation progresses (Akerele et al., 2020; Balogun et al., 2014; Hashimoto et al., 2017). These phenomena can be explained as follows (Fig. 1). The transcriptional regulation of the BDNF gene’s promoter activity is carried out via the phosphorylated PPARα-RXRα/CREB pathway. CREB is regulated by the phosphorylated PPARα-RXRα heterodimer, bound to its preferential agonist ligand DHA, at the transcriptional level. A PPAR-responsive element has been identified in the CREB promoter (Roy et al., 2013). Phosphorylation, exclusively on serine residues, increases the transcriptional activity of PPARα, via the-MAPK pathway (Majou, 2021). Upon activation by the Ca2⁺/calmodulin complex, activated CaM kinases autophosphorylate each other at threonine residue 286 (Ohsako et al., 1991). Phosphorylated CaMKII phosphorylates CREB at a particular residue, serine 133, and calcium-dependent phosphorylation of Ser133 is required for CREB-mediated transcription (Sheng et al., 1991). When activated, the CREB protein recruits other transcriptional coactivators, such as the coactivator CBP/p300, to bind to CRE promoter 5’s upstream region (Shaywitz et al., 1999; Yan et al., 2016).

Remarkably, BDNF seems to be capable of modulating its own expression levels in neurons, forming a transcriptional positive feedback loop (Esvald et al., 2020). BDNF-TrkB signaling may induce BDNF gene expression with the phosphorylation of CREB via the Shc (phosphorylated by BDNF/TrkB)/Shc/IRS-1/PI3K/Akt pathway (Peltier et al., 2007). We have been aware of the interaction between BDNF and sex steroids for decades, and some sex steroids, such as estrogen, have a positive regulatory effect on BDNF expression and signaling (Chan et al., 2017). Estrogens increase BDNF levels in the prefrontal cortex and the hippocampus (Luine et al., 2013). According to Spencer-Segal et al. (2012), free estradiol activates ERα, which mediates the effects on behaviors involving the hippocampus at least in part via Akt and TrkB signaling. These results are linked with the BDNF transcriptional autoregulation described above. We can hypothesize that free estradiol increases the phosphorylation of CREB via the PI3K-Akt signaling pathway. CREB phosphorylation appears to depend on basic brain activity (PI3K/Akt pathway) and stimulation (Ca2⁺/CaMKII pathway). The effects of these two pathways seem to be cumulative, modulated and limited (Fig. 1).

The precursor of BDNF, proBDNF, is packaged into regulated secretory pathway vesicles, processed and secreted in an activity-dependent manner. From plasminogen, which is cleaved by tissue plasminogen activator (tPA), the extracellular protease plasmin converts proBDNF to BDNF (Pang et al., 2004) and the BDNF pro-peptide, the N-terminal fragment of proBDNF. Only high-frequency neuronal activity induces tPA secretion (Van den Eijnden-Schrauwen et al., 1997), but it does not increase tPA mRNA levels (Gualandris et al., 1996). The Ca2⁺ signal of high glutamatergic activity is transduced to CaMKII (Bramham et al., 2007). BDNF vesicles are associated with carboxypeptidase E (CPE), a proneuropeptide/prohormone-processing enzyme, also known as neurotrophic factor-α1 (NFα1), in hippocampal and cortical neurons. The luminal domain of CPE’s membrane form acts as a receptor to sort BDNF into the regulated secretory pathway vesicles (Lou et al., 2005; Park et al., 2008). The regulation of CPE expression occurs through direct binding of PPARγ-RXRα to the CPE promoter (Thouennon et al., 2015).

tPA transcription is induced by the RARα-RXRα heterodimer (Bulens et al., 1995; Borel et al., 2010) with all-trans retinoic acid (ATRA) and 9-cis-retinoic acid for RARα and only 9-cis-retinoic acid, in competition with DHA, for RXRα. The induction is mediated by a specific retinoic acid response element (RARE) located in the promoter region of target genes. This tPA expression is also related to DHA. Indeed, PPARγ turns on retinoic acid synthesis by inducing the expression of retinol and retinal-metabolizing enzymes such as retinol dehydrogenase 10 (RDH10) and retinaldehyde dehydrogenase type 2 (RALDH2). PPARγ-regulated expression of these enzymes leads to an increase in the intracellular generation of ATRA from retinol. ATRA regulates gene expression via the activation of RARα (Gyöngyösi et al., 2013; Szatmari et al., 2006). It should be highlighted that the same mechanism exists for the expression of the TrkB gene. Retinoic acids induce a sustained increase in TrkB mRNA that is accompanied by an increase in TrkB mRNA transcription by the RARα-RXRα heterodimer (Lucarelli et al., 1995), and the PPARγ-RXRα heterodimer is involved in the same way, bound to its preferential agonist ligand DHA. The plasminogen activator inhibitor‐1 (PAI‐1) modulates tPA by inhibiting it through binding. Therefore, the tPA/PAI-1 system is an important regulator of the BNDF/proBDNF ratio. Increased PAI-1 expression and activity contribute to Aβ accumulation by inhibiting tPA (Liu et al., 2011) and impairing BDNF maturation (Gerenu et al., 2017). Conversely, the suppression of PAI-1 significantly reduces brain Aβ load (Akhter et al., 2018), and neuronal tau hyperphosphorylation is reverted (Gerenu et al., 2017). The PAI-1 inhibitors augment tPA and plasmin activity, and significantly lower plasma and brain Aβ levels (Jacobsen et al., 2008). The presence of c-Jun-responsive elements in the PAI-1 promoter has been reported (it is an AP-1-like binding site; Descheemaeker et al., 1992). However, DHA inhibits AP-1 and suppresses AP-1 activation (transcription factor activator protein 1; Liu et al., 2001; Zgórzyńska et al., 2021) via PPARɣ (Konstantinopoulos et al., 2007; Fig. 1). Thus, DHA is involved in the regulation and expression of tPA, as well as the inhibition of PAI-1, and consequently DHA boosts the action of BDNF.

Methyl-CpG-binding protein 2 (MeCP2) binds selectively to BDNF promoter III and represses the expression of the BDNF gene (Chen et al., 2003). The transcriptional regulation of BDNF by MeCP2 is controlled by MeCP2 phosphorylation on serine 421. CaMKII catalyzes this calcium-dependent phosphorylation event (Kolarow et al., 2007) and releases MeCP2 from BDNF promoter III, thereby facilitating the transcription and postsynaptic secretion of BDNF (Buchthal et al., 2012; Fig. 1). It is interesting to note that the level of stimulation (Ca2⁺ influx) modulates the regulation of proBDNF transcription via the release of MeCP2 and the phosphorylation of CREB, and then the conversion of proBDNF to BDNF via tPA. Above a certain concentration of Ca2, BDNF activity is modulated by (i) AMP-activated protein kinase (AMPK), whose activation by glutamate inhibits the effects of BDNF on protein synthesis by specifically suppressing the activation of mTOR (mechanistic target of rapamycin) signaling (Ishizuka et al., 2013) and (ii) AMPA receptors (glutamate receptors), which inactivate SULT2B1a, an enzyme that generates pregnenolone sulfate acting on NMDA receptors to accelerate the entry of Ca2⁺ (Fig. 1).

thumbnail Fig. 1

Role and regulation of BDNF.

3 DHA as a key regulator of BDNF’s action

The role of DHA in the expression of BDNF and in the actions of its protein has been the subject of several experiments. In adult rats or mice, a DHA-enriched diet increases levels of proBDNF and mature BDNF (Jiang et al., 2009; Sable et al., 2013; Sugasini et al., 2020; Vosadi et al., 2014; Wu et al., 2008), as well as in patients with schizophrenia, for example (Pawełczyk et al., 2019). The same applies to the CREB level (Wu et al., 2008). The opposite has also been suggested, i.e., that a DHA deficiency reduces BDNF expression in the frontal cortex, as well as CREB and MAPK activity (Rao et al., 2007). And a high-DHA maternal diet increases the mRNA expression of BDNF, TrkB and CREB, as well as the protein concentration of pCREB in the fetal-brain as gestation progresses (Akerele et al., 2020; Balogun et al., 2014; Hashimoto et al., 2017).

DHA plays an essential role as a gene transcription modulator via transcription factors, in particular peroxisome proliferator activated receptors (PPARs) and retinoid X receptors (RXRs). These transcription factors take the form of PPAR-RXR heterodimers, located within the nucleus and activated by phosphorylation (PPARα) and their respective ligands, which modify their tertiary structures and enable them to bind to the PPRE located in the promoter region of the target genes. DHA is a preferential ligand in comparison to PPARs and RXRs (de Urquiza et al., 2000; Deckelbaum et al., 2006; Diep et al., 2002; Dziedzic et al., 2018; Song et al., 2017). As we have already seen, CREB gene expression is regulated by the phosphorylated PPARα-RXRα heterodimer, and CPE gene expression is regulated by the PPARγ-RXRα heterodimer. DHA is involved in the regulation and expression of the tPA gene, as well as the inhibition of the PAI-1 gene, through PPARγ-RXRα (Fig. 1).

4 Conclusion

Neurons have high energy needs, requiring a continuous supply of glucose from the blood. Tight regulation of glucose metabolism in response to stimuli is essential for brain physiology. Glucose metabolism and cerebral blood flow are closely coordinated during neuronal activity to maintain proper brain function. The data and mechanisms presented above demonstrate the ability of BDNF-TrkB to stimulate glucose uptake in response to increased energy demand by increasing the expression of the neuronal glucose transporters (GLUTs) and NO-mediated vasodilation through the IGF-1/estradiol/PI3K/Akt signaling pathway. In short, high-frequency neuronal activity induces the secretion of BDNF, whose presence boosts this important pathway.

DHA, via the PPARα-RXRα and PPARɣ-RXRα heterodimers, is involved in the critical regulation of BDNF activation. As a preferential ligand of PPARs and RXR, DHA plays an important role in CREB and CPE gene expression, and it is involved in the regulation and expression of tPA, as well as the inhibition of PAI-1. BDNF boosts the IGF-1/estradiol/PI3K/Akt signaling pathway, and DHA boosts BDNF action.

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Cite this article as: Majou D, Dermenghem A-L. 2024. DHA (omega-3 fatty acid) increases the action of brain-derived neurotrophic factor (BDNF) OCL 31: 1.

All Figures

thumbnail Fig. 1

Role and regulation of BDNF.
In the text

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