The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis

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 (A 2a Rs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A 2a Rs, 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 A 2a Rs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A 2a Rs 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 A 2a Rs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.

Extracellular vesicles from human multipotent stromal cells protect against hearing loss after noise trauma in vivo

“…The latter receptor is activated by adenosine that in turn transactivates TrkB and enhances the promotion of neuronal survival. 62 CD73 is a 5'-ectonucleotidase that specifically cleaves adenosine monophosphate to release adenosine. CD73 is highly abundant in the membrane of MSC-derived EVs and surface profiling has confirmed the presence of CD73 in the MSC-EV preparations.…”

Ethionamide Preconditioning Enhances the Proliferation and Migration of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells

“…Previous reports suggested that PI3K/Akt and MEK/ERK1/2 signaling pathways regulate transcription activities including neurotrophic factors. The MEK/ERK1/2 pathway phosphorylates the transcription factor cAMP response element binding protein (CREB), which translocates into the nucleus and induces the transcription of BDNF and IGF-1 [ 55 , 56 , 57 , 58 ]. Recent studies have demonstrated that AKT and ERK1/2 also stimulate VEGF expression via HIF-1α activation [ 59 ] and that HGF production is upregulated by the RhoA-PI3K/Akt-MEK/ERK1/2 signaling axis [ 60 , 61 ].…”

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

“…Due to the relevance of the BDNF/TrkB signaling pathway in synapses' regulation and maintenance, especially regarding the NMJ, it has been studied in pathologies where synaptic function is impaired. Specifically, the BDNF/TrkB signaling is strongly impaired in brains affected by ALS, and all the approaches used around it were summarized in a recent review [94]. The present review summarizes how the retrograde BDNF/TrkB signaling pathway and the downstream alteration of protein kinases C is disturbed from its physiological mechanism in ALS at the NMJ and how exercise and other therapies that modulate kinases are effective at delaying ALS's progression.…”

“…Thus, this adds new evidence of the relevance of BDNF being able to work, which spotlights the importance of the mechanism of activation of TrkB, which depends on the TrkB.FL/TrkB.T1 ratio. Indeed, in the absence of BDNF, TrkB can be transactivated through A2R [110] and mAChR [90] and has been proposed as a therapy for neurodegenerative diseases [94].…”