Brain-derived neurotrophic factor (BDNF) is a central mediator of neuroplasticity, a term used to describe the ability of neurons to adapt in response to challenges, resulting in structural and functional changes to neurons (Huang et al, 2001). BDNF is the second member of the neurotrophin family to be identified, with nerve growth factor (NGF) discovered 3 decades prior (Barde et al, 1982; Levi-Montalcini and Hamburger, 1951). Several other neurotrophic factors have since been discovered, all possessing distinct functions in specified areas of the central nervous system (CNS) (Shen et al, 1997). BDNF is expressed throughout the CNS, although particularly high BDNF expression is found in the hippocampus and cerebral cortex, and is primarily expressed in neurons (Murrer et al, 1999; Conner et al, 1997).
The Role of BDNF in Neuroplasticity
Many studies have identified neurotrophins as critical modulators of neurogenesis (Zigova et al, 1998). BDNF specifically regulates axon and dendrite growth, receptor trafficking to the membrane, and the release of neurotransmitters, enabling synaptic transmission (Pease et al, 2000; Gottschalk et al, 1998; Segal et al, 1995). Multiple studies have demonstrated the essential role of BDNF in long term potentiation (LTP), with a fluctuation in BDNF levels during learning (Kesslak et al, 1998), and knockout studies showing increased cognitive impairment (Minichiello et al, 1999).
Structurally, BDNF is a homodimer and is composed of signal peptide sequence, and an N-glycosylation site. It is located in the nerve terminals and transported throughout the neuron in an anterograde fashion (Altar et al, 1997). Cleavage of BDNF must occur in order to assume its active role (Chao and Bothwell, 2002). Secreted BDNF binds to the tyrosine kinase receptor tropomyosin-related kinase B, also known as tyrosine-kinase B (trkB). Ligation of trkB induces its autophosphorylation and allows subsequent interactions between trkB and multiple cytoplasmic adaptor proteins, such as phospholipase C (PLC-g), culminating in the activation of MAPK and cyclic AMP-response element binding protein (CREB) pathways downstream (Patapoutian and Reichardt, 2001). Several studies have shown that BDNF can interact with a truncated from of trkB (Fryer et al, 1997), and it has been proposed that this binding activates a form of negative regulation of full-length trkB by sequestering BDNF (Haapasalo et al, 2001; Eide et al, 1996), although more recent studies have suggested that truncated trkB may also initiate signalling through RhoGTPases and Ca2+ -dependent pathways (Fenner et al, 2012; Rose et al, 2003).
The Role of BDNF in Mediating Inflammatory Signalling
BDNF signalling can modulate key pro-inflammatory transcription factors, such as NF-kB and AP-1, and limit the inflammatory response (Xu et al, 2017). Interestingly, pro-inflammatory cytokine stimulation downregulates BDNF expression in the hippocampus and cerebral cortex of mice (Guan and Fang, 2006; Lapchak et al, 1993), demonstrating bi-directional communication between BDNF and immune signalling, and also highlighting the impact of inflammatory pathogenesis on neuronal homeostasis. Additionally, there is evidence that glucocorticoids reduce BDNF, further linking the inflammatory response to neurotrophin levels (Gubba et al, 2004).
The Role of BDNF in Neuropathologies
BDNF is downregulated in response to acute and chronic stress and chronic inflammation(Jiang et al, 2011; Shi et al, 2010), and altered BDNF levels are also associated with the pathogenesis of depression (Zhang et al, 2014; Shimizu et al, 2003). Moreover, absence of the truncated form of trkB resulted in a delayed onset of Amyotrophic Lateral Sclerosis in mice (Yanpellewar et al, 2012). Additionally, reduced levels of BDNF are reported in schizophrenia (Chen da et al, 2009), and specifically in the hippocampi of Alzheimer’s disease (Burbach et al, 2004) and Parkinson’s disease pathogeneses (Howells et al, 2000). Elevated levels of BDNF are evident in epileptogenesis, with the inhibition of trkB, using anti-trkB antibodies resulting in reduced pathogenesis (Binder et al, 2009). However, BDNF has been demonstrated to exert anti-inflammatory and anti-apoptotic effects by downregulating NF-kB and AP-1 signal transduction in a bacterial meningitis model of disease, indicating the complexity of BDNF and the duality of its role which is apparently stimulus and disease specific (Xu et al, 2017). Another study demonstrated in a stroke model that BDNF exerts similar anti-inflammatory effects by upregulating IL-10 and downregulating TNFa, as a protective anti-inflammatory mechanism (Jiang et al, 2010). Increased metastasis has been described in neuroblastoma in a BDNF-MAPK dependent manner, highlighting the need to tightly control BDNF signalling in order to combat tumourigenesis (Hua et al, 2016). With the therapeutic potential of BDNF growing more attractive, small molecule BDNF mimics have been developed and have been successful in attenuating the pathology of traumatic brain injury (Wurzelmann et al, 2017). Increases in BDNF using molecular mimics to treat Alzheimer’s disease has also been explored (Leyhe et al, 2008). These exciting results have given a strong basis for the potential future success of BDNF modulation for the treatment of neurological disorders.
Figure 1: BDNF signalling. BDNF binds to the tyrosine kinase receptor B (trkB) initiating receptor autophosphorylation and the activation of the trkB kinase activity. Downstream binding to acitvators of MAPK, Akt, Ca2+ and CREB pathways leads to increases in neurogenesis, long-term potentiation and synaptic plasticity, as well as downregulation of immune signalling pathways via the transcription factors NF-kB and AP-1.
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