The Pleiotropic Potential of BDNF beyond Neurons: History
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Subjects: Endocrinology & Metabolism
Contributor:
Marianna Flora Tomasello

Brain-derived neurotrophic factor (BDNF) represents one of the most widely studied neurotrophins because of the many mechanisms in which it is involved. Among these, a growing body of evidence indicates BDNF as a pleiotropic signaling molecule and unveils non-negligible implications in the regulation of energy balance. In the hypothalamus, BDNF and its receptor are extensively expressed, in those regions where peripheral signals, associated with feeding and metabolism, are integrated to elaborate anorexigenic and orexigenic effects. Thus, BDNF coordinates adaptive responses to fluctuations in energy intake and expenditure, connecting the central nervous system with peripheral tissues, including muscle, liver, and adipose tissue in a complex operational network.

  • BDNF
  • hypothalamus
  • mitochondria
  • exercise
  • metabolism
  • energy balance
  • pleiotropic
  • neurons

1. Introduction

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family along with the nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4) [1]. BDNF is critically involved in neuronal development and synaptic plasticity; it promotes neuronal differentiation by stimulating neurite outgrowth and synapses formation, and it can prevent apoptosis [2].
For the crucial and physiological functions performed, the gene structure of BDNF is highly conserved throughout mammals and its transcription is tightly regulated and cell-type specific [1].
BDNF and its high-affinity receptor TrkB (tropomyosin-related kinase B) are widely expressed in the developing and mature central nervous system (CNS) and in many peripheral tissues, including muscle, liver, and adipose tissue [3].
BDNF is synthesized as pro-BDNF and converted into mature BDNF (mBDNF) by furin and proconvertases within intracellular vesicles. Neurons are able to release either mBDNF or pro-BDNF in response to numerous stimuli. The ratio between pro-BDNF and mBDNF changes during distinct developmental stages and postnatal life [1][4][5][6]. When released, pro-BDNF is converted by the tissue plasminogen activator/plasmin system into mBDNF or may act as an independent ligand preferentially on the neurotrophin receptor p75 (p75NTR), a member of the tumor necrosis factor family of receptors. Although with a much lower affinity, mBDNF is also able to bind the p75NTR. Notably, TrkB and p75NTR seem to mediate functionally antagonistic actions [1][2][7].
Once released, mBDNF forms stable homodimers and exerts its action locally, since its biochemical characteristics prevent the broad diffusion of the neurotrophin [1]. The binding of mBDNF to TrkB induces receptor dimerization and the autophosphorylation of tyrosine residues in the intracellular domain, which triggers a complex set of signaling cascades, specifically the tissue phospholipase C (PLC), phosphatidylinositol-3 kinase (PI3-K), and MAPK pathways. This results in the activation of specific transcriptional factors which in turn control the expression of proteins involved in plasticity, neuronal survival, cellular energy balance, and mitochondrial biogenesis. BDNF also upregulates antioxidant proteins, modulates cytoskeletal dynamism, and prevents apoptosis by promoting the expression of the anti-apoptotic Bcl-2 family members and inhibiting the pro-apoptotic ones [2][8].

2. The Role of BDNF in the Central Control of Energy Balance

Energy homeostasis is the result of a complex interplay between the brain and peripheral tissues. Neuronal circuitry in the hypothalamus and hindbrain receives and integrates peripheral signals related to hunger, satiety, and energy storage in the body and elaborate specific responses regulating nutrient intake and energy expenditure. Therefore, to maintain energy balance, organisms have to evaluate changes in energy needs considering several factors such as physical activity and thermoregulation. Hormones such as insulin, leptin, PYY, and ghrelin, allow this tightly regulated information exchange [9][10][11]. Alongside hormones, emerging players in the energy balance regulation are neurotrophins, most notably, BDNF and its receptor, both abundantly expressed in several regions of the hypothalamus and in the hindbrain [3][12].
The involvement of BDNF in the central regulation of feeding was noticed earlier during investigations aiming at improving the knowledge about how BDNF regulates learning, memory, synaptic transmission and plasticity [11]. The intracerebroventricular (ICV) injection of BDNF in rats to evaluate the neurotrophic effect in the treatment of Alzheimer’s also induced appetite suppression and weight loss [13][14]. In mice models of diabetes and obesity, BDNF administration produced anorexigenic effects, reduced blood glucose and increased pancreatic insulin content [15][16]. These data were also confirmed in BDNF heterozygous mice in which about half of them exhibited hyperphagic obesity; notably, chronic brain infusion of BDNF in obese BDNF-deficient mice was able to transiently reduce body weight [17]. BDNF involvement in the regulation of energy homeostasis was also reported in humans, in a young patient characterized by the early onset of obesity and hyperphagia along with developmental delays and other neurological defects. The young patient carried a heterozygous mutation in the NTRK2 gene, which encodes for the TrkB receptor. Namely, the mutation impinges on the activation loop of the TrkB catalytic domain (Y722C) leading to the loss of TrkB function [11][18]. Furthermore, mutations in the gene encoding BDNF are associated with eating disorders inducing obesity, hyperactivity as well as impaired cognitive functions. These data link BDNF to the regulation of energy homeostasis in humans [19][20][21] (Box 1 and Table 1).
Box 1. Genetic studies in humans carrying BDNF mutations.
Genetic disorders causing BDNF haploinsufficiency or TrkB inactivation provide direct evidence for the understanding of the role of BDNF in the regulation of energy balance in humans. A deficit in BDNF expression or in its signalling may contribute to weight gain and cognitive impairment which vary in phenotypic severity [22][23].
Gray et al. identified a chromosomal inversion encompassing BDNF gene in an 8-year-old girl with hyperphagia, severe obesity, hyperactivity and cognitive impairment. The chromosomal inversion affected BDNF expression with a loss of function without disrupting the sequence of the gene itself [19]. An additional study reported a BDNF haploinsufficiency in a cohort of patients with WAGR syndrome, a rare genetic disorder caused by contiguous gene deletions on chromosome 11p13 region of varying size. Since the BDNF gene is located in the chromosomal locus 11p14.1, approximately half of the patients with WAGR syndrome had a heterozygous BDNF deletion. In these subjects, BDNF haploinsufficiency was significantly associated with a rise in body mass index, hyperphagia and reduced BDNF levels in serum along with neurocognitive impairments [20]. Similarly, low levels of serum BDNF were reported in patients with metabolic and eating disorders [24][25].
Several genome-wide association studies have strengthened these findings identifying BDNF single nucleotide polymorphisms (SNPs) linked to an increased risk of developing obesity in humans. The most commonly studied BDNF SNP is the G196A variant which causes the substitution of valine with methionine in the pro-BDNF position 66 (Val66Met). The amino acid change affects the intracellular trafficking and packaging of pro-BDNF impinging the activity-dependent secretion of mBDNF [22][26][27][28]. A rare de novo missense variant in BDNF and seven NTRK2 mutations along with three variants previously reported [23] have also been functionally characterized by Sonoyama et al. Clinical data collected from carriers of BDNF/TrkB variants showed in addition to severe obesity, a spectrum of neurobehavioral disorders such as hyperactivity, learning deficit and shot-term memory impairment [29]. Interestingly, a latest study reports an atypical Charcot–Marie–Tooth disease type 2Q phenotype with obesity likely related to the mutation identified in the coding region of the NTRK2 gene [30].
All things considered, there is clear evidence of the crucial role of BDNF in modulating body weight and energy homeostasis, although further studies are needed to better elucidate the BDNF involvement in these syndromes (Table 1).
Table 1. Clinical studies on common and rare variants in BDNF and NTRK2.
Gene Mutations Phenotypic Features Reference
BDNF 11p inversion; haploinsufficiency Severe obesity, hyperphagia, impaired cognitive function, hyperactivity [19] Gray, J. et al., 2006
[22] Han, J.C., 2016
Deletions including the 11p14 BDNF locus among patients with WAGR syndrome; haploinsufficiency Obesity, hyperphagia, lower levels of serum BDNF [20] Han, J.C. et al., 2008
[22] Han, J.C., 2016
Intronic SNP: rs12291063 CC genotype Obesity [21] Mou, Z. et al., 2015
SNP rs6265 commonly known as G196A => Val66Met Susceptibility to obesity, several psychiatric conditions including eating disorders [25] Rosas-Vargas, H. et al., 2011
[26] Vidović, V. et al., 2020
[27] Ieraci, A. et al., 2020
[22] Han, J.C., 2016
Missense mutation E183K Severe obesity and moderately learning difficulties [29] Sonoyama, T. et al., 2020
NTRK2 Missense mutation Y722C Severe early-onset obesity, hyperphagia, developmental delay [18] Yeo, G.S.H. et al., 2004
Missense mutations: I98V, P660L, T821A Severe obesity, developmental delay [23] Gray, J. et al., 2007
Missense mutations: P204H, R691H, R696K, S714F, R715Q, R715W, P831L Severe obesity, hyperactivity, maladaptive behaviours and impaired short-term memory [29] Sonoyama, T. et al., 2020
In the hypothalamus, BDNF is synthesized in several regions participating in metabolic homeostasis, including the ventromedial hypothalamic nucleus (VMH), the dorsomedial hypothalamic nucleus (DMH), the paraventricular nucleus (PVH) and the lateral hypothalamic area (LH). The arcuate nucleus (ARC), a crucial hypothalamic center controlling energy balance, does not seem to be involved in BDNF synthesis but in its function [3][11]. In fact, TrkB is expressed in the ARC, which in turn, displays two functionally different populations of neurons: (i) cells producing the anorexigenic polypeptides cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC), a precursor of α-melanocyte stimulating hormone (α-MSH), the ligand of melanocortin receptor 4 (MC4R), and (ii) cells producing the orexigenic neuropeptide Y (NPY) and the agouti-related protein (AgRP), an antagonist of MC4R [10][12]. Metabolic and nutritional signals mediated by peripheral factors are integrated in this region which is connected to other hypothalamic nuclei crucial in the control of feeding. Notably, BDNF seems to be essential in promoting axonal projections of TrkB expressing neurons from ARC to the PVH and DMH [31]. An earlier study also showed a link between the local translation of BDNF in hypothalamic neuronal dendrites and the activity of leptin and anorexigenic hormone released by adipose tissue [32][33].
The VMH represents the principal region where BDNF is produced in response to finely tuned stimuli integrated from nutritional cues such as glucose, leptin or fasting. Unger and collaborators demonstrated that glucose administration in adult mice induced an increase in both BDNF and TrkB levels in VMH and that the deletion of the BDNF gene in the VMH and DMH produced hyperphagic obesity without changing energy output and locomotion. Thus, the VMH and DMH have been pinpointed as important sources of BDNF for the regulation of satiety and appetite suppression [34]. It was also shown that BDNF expression in VMH is upregulated in response to leptin [35] and modulated by MC4R signaling [36]. In particular, the evidence that: (i) a MC4R agonist largely raised BDNF mRNA levels in the VMH following a period of food deprivation and (ii) the brain infusion of BDNF restored a normal feeding behavior in mice deficient of MC4R signaling and fed with a high-fat diet (HFD) suggested the presence of circuitry in which BDNF represents a downstream effector of MC4R signaling [36][37]. To date, the mechanism regulating the synthesis of BDNF is still unclear. BDNF expression could be directly mediated by specific cues, as described above, and/or indirectly triggered via the action of relevant stimuli acting on circuits connecting hypothalamic nuclei each other [11][35].
Similar results were achieved in the dorsal vagal complex (DVC) of the hindbrain. Studies in adult rats provide evidence that BDNF delivery in the DVC negatively regulates food intake and that BDNF/TrkB signaling could mediate the action of melanocortins and could contribute to the leptin anorexic effect [38][39][40].
The key role of BDNF in regulating energy balance was also investigated in the PVH. In particular, the injection of BDNF in this region caused a loss of body weight in rats by reducing food intake and promoting energy expenditure as a consequence of an increased resting metabolite rate, likely associated with the thermogenic effect of the uncoupling protein 1 (UCP1) in the brown adipose tissue (BAT) [41][42]. Alongside the regulation of food intake, the involvement of BDNF in energy expenditure may also be mediated through the control of BAT thermogenesis and locomotor activity. In particular, by assessing the effect of the BDNF ablation in the PVH, An et al. revealed the presence of discrete neuronal populations associated with different functions, for example, BDNF neurons in the anterior PVH related to hyperphagia and reduced locomotor activity and BDNF neurons in medial and posterior PVH promoting thermogenesis through polysynaptic connections with the BAT [43]. In a follow-up study, the same authors, using a projection-specific gene deletion approach, accurately investigated the action site of PVH neurons expressing TrkB and identified neuronal networks with the VMH and lateral parabrachial nucleus (LPBN) involved in appetite suppression [44].Energy consumption mediated by thermogenesis and physical activity was furthermore induced by the activation of neurons that express TrkB in the DMH. This recent study revealed distinct neuronal populations expressing TrkB which create neurocircuitry by projections to several brain regions (raphe pallidus, PVH and preoptic area) to accurately manage energy expenditure and food intake [45]. The more significant studies investigating the role and the effects of BDNF in the central control of energy balance are summarized below (Table 2).
Table 2. The more significant studies investigating the role and the effects of BDNF in the central control of energy balance in rodents’ models.
Animal Model Intervention/Stimuli Effects Reference
Wistar rats Chronic intraventricular administration of BDNF and NGF Reduction in weight gain [13] Lapchak, P.A.; Hefti, F., 1992
Long-Evans rats ICV BDNF infusion
(lateral ventricle)		 Appetite suppression and weight loss [14] Pelleymounter, M.A et al., 1995
C57BL/KsJ-db/db mice
(obese diabetic mice)		 BDNF central (ICV) administration Reduction in blood glucose and increase in pancreatic insulin [15] Nonomura, T. et al., 2001
C57BL/KsJ-db/db mice (obese diabetic mice);
streptozotocin-induced type 1 diabetic mice;
KK mice (normoglycemic obese mice with impaired glucose tolerance)		 BDNF central (ICV) and subcutaneous administration Antidiabetic effects [16] Nakagawa, T. et al., 2000
BDNF mutant mice (obese BDNF heterozygous mice) BDNF central administration (third ventricle) Transient reversion of eating behaviour and obesity [17] Kernie, S.G. et al., 2000
Bdnfklox/klox mice (deficiency in long 3′ UTR Bdnf mRNA/severe obesity development) Viral expression of long 3′UTR Bdnf mRNA in the hypothalamus (VMH) Complete rescue of hyperphagic obesity [32] Liao, G.-Y. et al., 2012
Wild-type mice Intraperitoneal and ICV administration of glucose after 48h fasting period Increase in BDNF and TrkB mRNA in VMH [34] Unger, T.J. et al., 2007
BDNF central administration (third ventricle) Neurons activation in hypothalamic appetite-regulating centers
Bdnf 2L/2L mice Selectively deletion (viral-mediated) of BDNF alleles in the VMH and DMH Hyperphagic behavior and obesity
C57BL/6J mice ICV leptin administration Increase in BDNF mRNA in the dorsomedial part of VMH [35] Komori, T. et al., 2006
Wild-type mice Injection of a MC4R agonist (MTII) into the dorsal third ventricle after a 44 h fasting period Increase in BDNF mRNA in the VMH [36] Xu, B. et al., 2003
Wistar Han rats Intraparenchymal infusion of BDNF in the DVC Anorexia and weight loss [38] Bariohay, B. et al., 2005
Peripheral leptin injection Increase in BDNF protein content within the DVC
Wistar Han rats BDNF ICV injection into the DVC (4th ventricle) Reduction in food intake [39] Bariohay, B. et al., 2009
ICV delivery of a MC3/4R agonist (MTII) into the DVC (4th ventricle) Increase in the BDNF protein content in the DVC
ICV delivery of a MC3/4R antagonist (SHU9119) into the DVC (4th ventricle) Decrease in the BDNF protein content in the DVC
Sprague-Dawley rats ICV (4th ventricle/hindbrain) BDNF injection Reduction in cumulative food intake and body weight; increase in core temperature [40] Spaeth, A.M. et al., 2012
Intraparenchymal injection of BDNF into the medial nucleus tractus solitarius (mNTS) Suppression of food intake and body weight
Intraparenchymal delivery of BDNF into the mNTS after ANA-12 (specific TrkB receptor antagonist) preadministration Inhibition of the intake-suppressive effect of BDNF
ICV (4th ventricle/hindbrain) leptin injection Increase in the BDNF protein content within the DVC tissue
Sprague-Dawley rats BDNF injection into the PVH Decrease in feeding and body weight; increase in energy expenditure; UCP1 expression increase in BAT [41] Wang, C. et al., 2007

3. The Role of BDNF in the Peripheral Control of Energy Balance

In the previous paragraphs, we have discussed the BDNF involvement in the regulation of energetic metabolism and the way it is achieved through the modulation of the mitochondrial function, related to physical exercise. Alongside these concepts, BDNF seems to actively participate in nutrient uptake control in different types of cells, thus defining the differentiation of the given cell type toward a distinct physiological function.
Energy requests, both in the basal state and during exercise, are covered by two major substrates: glucose and free fatty acids (FFA). Conversely, protein oxidation occurs for the protein taken with the diet and contributes 10% to 15% of TEE. Glucose and FFA can be considered interchangeable as intermediate metabolites in most tissues, but the brain relies almost exclusively on glucose metabolism [46].
During postnatal brain development, BDNF signaling increases glucose and amino acid uptake, playing a determinant role in the response to the increased energy demand and protein synthesis associated with neuronal differentiation. In fact, in the brain, 50% of the total energy consumption is used to restore ion gradients and resting membrane potentials by Na+/K+-ATPase [47] useful to synaptic plasticity and electrical stimulation. Notably, in cortical neurons, 20 min BDNF exposure increases GLUT3 (neuronal glucose transporter) mRNA and protein levels, thus enhancing glucose utilization by increasing its uptake. This effect requires TrkB receptor activation and the PLC signaling pathway and is specific for cortical neurons since it is not described in cortical astrocytes [48].
BDNF participates in the regulation of peripheral energy metabolism by directly acting on those cells which are strictly involved in the glucose homeostasis such as pancreatic β cells and hepatocytes [49].
In peripheral tissues, glucose homeostasis is under the regulation of insulin signaling. In fact, in the liver of diabetic mice, BDNF treatment enhances the tyrosine phosphorylation of the insulin receptor which in turn trigger PI3-K signaling [50][51]. The reduction in blood glucose levels is associated with an increase in the number and total area of pancreatic islets and with an increase in secretory granules in β-cells [52]. It has been demonstrated that the synergistic effect of BDNF and glucose levels induces insulin release from pancreatic β-cells. In mice, the synergistic effect happens when blood glucose levels are high; in humans, insulin is released from islets, even in the presence of lower blood glucose levels. This is likely due to the intrinsic differences between mouse and human β-cells. Notably, their sensitivity to glucose as well as the expression of different ion channels, might influence β-cell sensitivity to intracellular Ca2+ levels induced by BDNF/TrkB signaling [53].
Furthermore, glucagon levels seem to be influenced by BDNF. Infusion of BDNF into the rat brains results in decreased glucagon levels in the portal vein. This effect is abrogated by the denervation of pancreatic efferent nerves [54]. Moreover, it is observed that the intraportal administration of GLP-1 (glucagon-like peptide 1) increases BDNF levels in the pancreas and reduces glucagon secretion. GLP-1 receptors are expressed in the pancreas, muscle, liver and also in neurons throughout the brain. The activation of GLP-1 receptors results in cyclic AMP production and in the activation of CREB which is known to induce BDNF expression. Similar to GLP-1, BDNF signaling increases glucose uptake by liver, skeletal and cardiac muscle cells [55].
BDNF might also be considered as an adipokine since it is expressed in both BAT and WAT [56][57]. In particular, significant changes in BDNF and NTRK2 expression are observed in the adipose tissue of obese mice (NTRK2 is downregulated by adipocytes, in contrast, BDNF is upregulated by other cells) implying that BDNF may have a role in the regulation of systemic metabolism [58] Other studies, performed in rats, demonstrated the activation of BDNF and TrkB-expressing neurons located in sympathetic outflow circuitry that ultimately innervate WAT, the tissue where lipolysis is stimulated. This sympathetic activation is responsible for the increase in circulating FFA and glycerol concentrations and for the decrease in body fat mass [59].
All these literature data allow the consideration of BDNF as a metabolic modulator that coordinates the adaptive response of the brain and the body to fluctuations in energy intake and expenditure; for this reason, it was defined as “metabokine”, meaning a pleiotropic signaling molecule [60].
In hypothalamic neurons, BDNF influences food intake through the activation of mTORC1 (mTOR complex 1). Similar to insulin, BDNF binds tyrosine kinase receptor, thus activating the PI3-K/Akt pathway [28][61][62]. The activation of mTORC1 stimulates protein synthesis and lipid biosynthesis resulting in cellular mass gain and reduced food intake needs. Notably, it is demonstrated that BDNF can act through different signal transduction pathways, mTOR and AMPK, although they work oppositely (i.e., when intracellular energy is abundant, mTOR activity is increased and AMPK activity is decreased, and vice versa) [63][64]. The types of signaling pathway activated depend on the tissue where BDNF acts. In myotubes and in contracting muscle BDNF promotes catabolic pathways, increasing β-oxidation through AMPK signaling that activates acetyl coenzyme A carboxylase (ACCβ) and consequently enhances fat oxidation and inhibits fat synthesis [65][66][67]. Similarly, in hepatocytes, BDNF activates the same molecular mechanism but this results in increased fatty acid oxidation, glycogen storage and inhibition of gluconeogenesis [68].

4. BNDF Involvement in Neurodegenerative Disorders

It is known that the pathos-physiological modifications associated with several neurodegenerative diseases begin decades before the emergence of clinical symptoms. One of these changes is the impairment in the brain energy metabolism. The brain, indeed, has high energy requirements, as it employs most of the glucose for the maintenance of synaptic functions and of neuronal resting potentials. As broadly discussed throughout this manuscript, among other functions, BDNF is closely involved in the regulation of energy balance, and BDNF levels are influenced by physical activities. Alongside being essential for the survival and phenotypic maintenance of mature, fully developed neurons, BDNF is recognized to modulate several neuronal functions, such as axonal growth, long-term potentiation, which is pivotal for the development of learning and memory. Therefore, it is not surprising that BDNF is implicated in several neurodegenerative diseases, including Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD) diseases, and other neuropsychiatric disorders [69][70].
The first evidence implicating BDNF in AD and PD dates back to the 1990’s, and for both pathologies, reduced levels of mRNA or proteins were described either in postmortem brains of humans or mice models [71][72][73][74]. Lower BDNF mRNA expression was reported in the hippocampus, neocortex, in the Meynert nucleus basalis, all of which are regions selectively vulnerable to the degeneration in AD [72]. Reduced BDNF levels were also associated to the presence of neurofibrillary tangles, a hallmark of AD [75]. Accordingly, the withdrawal of BDNF in cultured hippocampal neurons or BDNF depletion in mice also resulted in differential expression of genes implicated in AD. More importantly, genetic delivery of BDNF in primate and rodent models of ADreduce synaptic loss and improve learning and memory formation [76].
As in AD, reduced expression of BDNF mRNA and protein are found in dopaminergic neurons of the substantia nigra, a region of the brain where PD-affected neurons are localized [72][77][78]. This notion was confirmed when many classical features of animal PD models were reproduced by blocking the BDNF expression in the substantia nigra of rats [79]. Accordingly, Wnt-BDNFKO mice, completely lacking BDNF in the midbrain and hindbrain, show a persistent reduction of dopaminergic neurons in the substantia nigra [80]. In addition, reduced BDNF production is closely associated with pathogenic mutations in α-synuclein in familial PD [81][82].
The assessment of BDNF levels in human postmortem cerebral cortex samples indicated that BDNF production was also impaired in the brains of HD patients [83][84]. Several works confirmed the reduction of BDNF levels in a large panel of huntingtin (Htt) knock-out mice, indicating that a decrease in cortical BDNF levels occur early in the disease and that it is partly due to the lower stimulatory activity of wild type Htt. Indeed, the increase or decrease in wild-type Htt levels in mouse models augments or reduces, respectively, the transcription from the BDNF promoter [85][86]. Accordingly, Htt is thought to play a role in the transport and activity-dependent release of BDNF [85][87]. Thus, mutations in the Htt protein result in “loss of function”, greatly affecting BDNF levels in striatal neurons.
BDNF is reported to slow the progression of motor neuron atrophy in an animal model of amyotrophic lateral sclerosis (ALS) [88], and the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) improved motor neuron deficits in the superoxide dismutase 1 (SOD1G93A) ALS mouse models [89].
Recent clinical studies have also demonstrated an association between low levels of BDNF and depressive disorders. Accordingly, BDNF infusion produces anti-depressive-like effects in the mouse midbrain of depression mice models [90]. Finally, in the hippocampus, prefrontal cortex, anterior cingulate cortex and superior temporal gyrus of schizophrenia patients, BDNF mRNA and protein levels have been found to be lower than in the controls [91][92][93].
The above-mentioned findings, which demonstrated that levels of neurotrophins influence the progression of neurodegenerative disorders, are the rationale for developing therapeutic approaches based on the modulation of BDNF levels.
The first clinical trial considering the application of BDNF infusions in neurodegenerative diseases was performed in ALS patients but failed to demonstrate a statistically significant effect of BDNF on patients survival [94][95]. It is possible that the poor pharmacokinetics associated with the intact protein, the BDNF short in vivo half-life, the limited diffusion and low penetrability of the blood-brain barrier has hindered progress towards a therapeutic strategy. Consequently, since pharmacological treatments are not available, other remedies are found to delay the course of the disease: physical exercise, enriched environment, hormonal balance (i.e., steroid hormones such a cortisol and testosterone) and nutritional intervention (i.e., fasting, low-calorie intake, low-carb diet, selective nutrient intakes). Among them, epidemiological studies have found that physical activity reduces the risk of AD and dementia by 45% and 28%, respectively [96] and are capable to rescue BDNF levels [97]. In agreement with these results, preliminary findings indicate that in healthy individuals the deposition of plaque/tangle in the brain inversely correlate with an healthy life style (normal body weight, regular physical activity, and healthy diet) [98].
The research on neurodegenerative diseases discussed above, strengthens the concept that BDNF levels are influenced by physical activities. However, the underlying molecular mechanisms explaining these findings are unknown. Based on findings from animal models, Mattson proposed that physical activity and intermittent energy restriction can together hinder neurodegenerative processes and improve brain function supporting the neuronal adaptive stress response including DNA repair, neurotrophic signaling, mitochondrial biogenesis [99]. Physical exercise downregulates Bax and neuro-inflammatory cytokines in the hippocampus [100][101], reduces chronic oxidative stress and promotes mitochondrial biogenesis. Porrit and collaborators [79] reported that BDNF overexpression decreases the expression of PINK1, an integral protein that governs mitochondrial quality control [102], and restores the activity of key enzymes (complex I, complex II+III) in the mitochondrial respiratory chain. Others have shown that the pathways by which exercise-induced neuronal BDNF might involve the co-activation of PGC-1α, leading to the activation of fibronectin type III domain-containing protein 5 (Fndc5) gene expression [103]. Accordingly, exercise is known to enhance the activities of BDNF regulating transcription factors CREB and NF-κB [104] which can act in cooperation with FNDC5. On the other hand, several reports indicate that factors enhancing glucose uptake and glycolytic flux (e.g., Wnt3a) or regulating mitochondrial functions could be beneficial in AD, PD, ALS and in other neuropathological conditions [105].
From a unitary perspective, brain metabolism is intended to equate oxygen consumption to glucose utilization. However, the concept of increased non-oxidative glucose consumption during physiologic neural activity has recently gained a lot of consideration. Enhanced aerobic glycolysis and increased lactate production are recognized as common properties of invasive cancers and its up-regulation in cancer results in the suppression of apoptosis. This phenomenon, termed the Warburg effect, is progressively being recognized as well in the CNS as an adaptive response that would provide selective advantages for neuronal survival. Our group previously reported on a neuroprotective effect of monomeric Aβ in vitro which is directly connected to the regulation of glucose utilization in neurons [106]. This effect mediated by the IGF-IR and the ensuing PI3K pathway, results from the stimulation of the CREB target genes including BDNF [107]. Most recently, we have demonstrated that in response to the inhibition of oxidative phosphorylation, cultured cortical neurons increased aerobic glycolysis. This increase depends on the stimulation of the PI3K pathway and involves the activation of AKT, a master regulator of survival/apoptosis which targets various proteins including hexokinase (HK). HK is mainly associated with the outer mitochondrial membrane [108]. Mitochondrial-bound HKI supports neurons and the HK-released from mitochondria decreases in enzyme activity and triggers apoptosis in cells.
On these premises, we speculate that, by stimulating specific pathways, BDNF prompts neurons to exploit either oxidative phosphorylation or aerobic glycolysis in order to quickly fuel neurons with the necessary energy to properly absolve their functions. This would represent a physiological homeostatic mechanism to ensure synaptic plasticity. Consequently, a reduction in BDNF and other neurotrophins, as occurring in aging and in diverse neuropathological conditions, might impair the neuronal ability to cope with transient needs in energy provision.

This entry is adapted from the peer-reviewed paper 10.3390/life11111256

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