Abstract
Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A2aRs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A2aRs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A2aRs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A2aRs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A2aRs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.
Highlights
Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND), is a fatal adult onset neurodegenerative disease resulting in progressive and preferential degeneration and death of upper motor neurons (UMNs, corticospinal neurons) of the motor cortex, and alpha lower motor neurons (LMNs) of the brain stem and the spinal cord (Cleveland and Rothstein, 2001; Turner et al, 2013)
This review focuses on the biology of Brain derived neurotrophic factor (BDNF) and its proposed neurotrophic and neurotoxic roles in the pathogenesis and treatment of ALS
One full- length tropomysin related kinase B (TrkB) (TrkB) contains an extracellular transmembrane domain, consisting of a cysteine rich cluster followed by 3 leucine repeats, a cysteine cluster followed by 2 immunoglobulin (Ig1 and Ig2) domains; and an intracellular cytoplasmic tyrosine kinase domain acting as a phosphorylation dependent docking site (Schneider and Schweiger, 1991; Tejeda and Diaz-Guerra, 2017)
Summary
Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). BDNF/TrkB neuroprotective functions can be elicited indirectly via activation of adenosine 2A receptors (A2aRs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A2aRs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). There is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. Direct inhibition of TrkB and A2aRs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A2aRs receptors may be important in early disease pathogenesis in ALS.
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