Brain-derived neurotrophic factor
Brain-derived neurotrophic factors, or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor, a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.
BDNF activates the TrkB tyrosine kinase receptor.
Function
BDNF acts on certain neurons of the central nervous system and the peripheral nervous system expressing TrkB, helping to support survival of existing neurons, and encouraging growth and differentiation of new neurons and synapses. In the brain it is active in the hippocampus, cortex, and basal forebrain areas vital to learning, memory, and higher thinking. BDNF is also expressed in the retina, kidneys, prostate, motor neurons, and skeletal muscle, and is also found in saliva.BDNF itself is important for long-term memory.
Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active. Mice born without the ability to make BDNF have developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development. Other important neurotrophins structurally related to BDNF include NT-3, NT-4, and NGF.
BDNF is made in the endoplasmic reticulum and secreted from dense-core vesicles. It binds carboxypeptidase E, and disruption of this binding has been proposed to cause the loss of sorting BDNF into dense-core vesicles. The phenotype for BDNF knockout mice can be severe, including postnatal lethality. Other traits include sensory neuron losses that affect coordination, balance, hearing, taste, and breathing. Knockout mice also exhibit cerebellar abnormalities and an increase in the number of sympathetic neurons.
Certain types of physical exercise have been shown to markedly increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise-induced neurogenesis and improvements in cognitive function. Niacin appears to upregulate BDNF and tropomyosin receptor kinase B expression as well.
Mechanism of action
BDNF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkB and the LNGFR. It may also modulate the activity of various neurotransmitter receptors, including the Alpha-7 nicotinic receptor. BDNF has also been shown to interact with the reelin signaling chain. The expression of reelin by Cajal–Retzius cells goes down during development under the influence of BDNF. The latter also decreases reelin expression in neuronal culture.TrkB
The TrkB receptor is encoded by the NTRK2 gene and is member of a receptor family of tyrosine kinases that includes TrkA and TrkC. TrkB autophosphorylation is dependent upon its ligand-specific association with BDNF, a widely expressed activity-dependent neurotrophic factor that regulates plasticity and is dysregulated following hypoxic injury. The activation of the BDNF-TrkB pathway is important in the development of short-term memory and the growth of neurons.LNGFR
The role of the other BDNF receptor, p75, is less clear. While the TrkB receptor interacts with BDNF in a ligand-specific manner, all neurotrophins can interact with the p75 receptor. When the p75 receptor is activated, it leads to activation of NFkB receptor. Thus, neurotrophic signaling may trigger apoptosis rather than survival pathways in cells expressing the p75 receptor in the absence of Trk receptors. Recent studies have revealed a truncated isoform of the TrkB receptor may act as a dominant negative to the p75 neurotrophin receptor, inhibiting the activity of p75, and preventing BDNF-mediated cell death.Expression
The BDNF protein is encoded by a gene that is also called BDNF, found in humans on chromosome 11. Structurally, BDNF transcription is controlled by eight different promoters, each leading to different transcripts containing one of eight untranslated 5' exons spliced to the 3' encoding exon. Promoter IV activity, leading to the translation of exon IV-containing mRNA, is strongly stimulated by calcium and is primarily under the control of a Cre regulatory component, suggesting a putative role for the transcription factor CREB and the source of BDNF's activity-dependent effects.There are multiple mechanisms through neuronal activity that can increase BDNF exon IV specific expression. Stimulus-mediated neuronal excitation can lead to NMDA receptor activation, triggering a calcium influx. Through a protein signaling cascade requiring Erk, CaM KII/IV, PI3K, and PLC, NMDA receptor activation is capable of triggering BDNF exon IV transcription. BDNF exon IV expression also seems capable of further stimulating its own expression through TrkB activation. BDNF is released from the post-synaptic membrane in an activity-dependent manner, allowing it to act on local TrkB receptors and mediate effects that can lead to signaling cascades also involving Erk and CaM KII/IV. Both of these pathways probably involve calcium-mediated phosphorylation of CREB at Ser133, thus allowing it to interact with BDNF's Cre regulatory domain and upregulate transcription. However, NMDA-mediated receptor signaling is probably necessary to trigger the upregulation of BDNF exon IV expression because normally CREB interaction with CRE and the subsequent translation of the BDNF transcript is blocked by of the basic helix–loop–helix transcription factor protein 2. NMDA receptor activation triggers the release of the regulatory inhibitor, allowing for BDNF exon IV upregulation to take place in response to the activity-initiated calcium influx. Activation of dopamine receptor D5 also promotes expression of BDNF in prefrontal cortex neurons.
BDNF-AS
The genomic locus encoding BDNF is structurally complex and also encodes BDNF-antisense. BDNF-AS is a long non-coding RNA transcribed from the opposite strand of the BDNF gene. This lncRNA was identified in 2005 through searches in expressed sequence tag databases and subsequent RT-PCR experiments. The gene encoding BDNF-AS is located on chromosome 11p14.1. BDNF mRNA and BDNF-AS share a common overlapping region and form double-stranded RNA duplexes.BDNF-AS regulates BDNF expression and can suppress BDNF mRNA. In the human neocortex, regions with increased activity and BDNF expression exhibit reduced BDNF-AS expression. Elevated BDNF-AS levels are associated with reduced BDNF expression and have been shown to promote neurotoxicity, increase apoptosis, and decrease cell viability. Conversely, inhibiting BDNF-AS upregulates BDNF mRNA, activates BDNF-mediated signaling pathways, increases BDNF protein levels, suppresses neuronal apoptosis, and promotes neuronal outgrowth and differentiation.
The BDNF-AS gene consists of 10 exons and a functional promoter upstream of exon 1. The BDNF-AS gene generates numerous distinct non-coding RNAs through alternative splicing. This diversity of spliced isoforms is a common feature of eukaryotic organisms, particularly in the nervous system. Notably, BDNF-AS is absent in rodents, although highly homologous sequences are present in the genomes of chimpanzees and rhesus monkeys, suggesting a primate/hominid evolutionary origin of BDNF-AS.
Variations in both the BDNF and BDNF-AS genes are important factors to consider, given their potential to alter BDNF function and contribute to multiple human phenotypes influencing disease susceptibility and treatment outcomes.
Common SNPs in BDNF gene
BDNF has several known single nucleotide polymorphisms, including, but not limited to, rs6265, C270T, rs7103411, rs2030324, rs2203877, rs2049045 and rs7124442. rs6265 is the most studied SNP in the BDNF gene.Val66Met
A common SNP in the BDNF gene is rs6265. This point mutation in the coding sequence, a guanine to adenine switch at position 196, results in an amino acid switch: valine to methionine exchange at codon 66, Val66Met, which is in the prodomain of BDNF. Val66Met is unique to humans.The mutation interferes with normal translation and intracellular trafficking of BDNF mRNA, as it destabilizes the mRNA and renders it prone to degradation. The proteins resulting from mRNA that does get translated, are not trafficked and secreted normally, as the amino acid change occurs on the portion of the prodomain where sortilin binds; and sortilin is essential for normal trafficking.
The Val66Met mutation results in a reduction of hippocampal tissue and has since been reported in a high number of individuals with learning and memory disorders, anxiety disorders, major depression, and neurodegenerative diseases such as Alzheimer's and Parkinson's.
A meta-analysis indicates that the BDNF Val66Met variant is not associated with serum BDNF.