AUTHOR=Fonseca-Gomes João , Jerónimo-Santos André , Lesnikova Angelina , Casarotto Plinio , Castrén Eero , Sebastião Ana M. , Diógenes Maria J. 

TITLE=TrkB-ICD Fragment, Originating From BDNF Receptor Cleavage, Is Translocated to Cell Nucleus and Phosphorylates Nuclear and Axonal Proteins

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 12 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00004

DOI=10.3389/fnmol.2019.00004

ISSN=1662-5099

ABSTRACT=The signalling of Brain-Derived Neurotrophic Factor (BDNF) has been suggested to be impaired in Alzheimer´s disease (AD), which may compromise the function of BDNF upon neuronal activity and survival. Accordingly, decreased levels of BDNF and its TrkB Full-Length receptor (TrkB-FL) have been detected in human brain samples of AD patients. We have previously found that neuronal exposure to Aβ peptide, a hallmark of AD, leads to calpain overactivation and subsequent TrkB-FL cleavage leading to decreased levels of TrkB-FL and the generation of two new fragments: a membrane-bound truncated receptor (TrkB-T’) and an intracellular fragment (TrkB-ICD). Importantly, we identified this TrkB-FL cleavage and TrkB-ICD presence in human brain samples, which indicates that this molecular mechanism contributes to the loss of BDNF signalling in humans. The exact role of this TrkB-ICD fragment is, however, unknown. Here, we used a human neuroglioma cell line and rat cortical primary neuronal cultures to track TrkB-ICD intracellularly. Our data show that TrkB-ICD is a relatively stable fragment that accumulates in the nucleus over time, through a phosphorylation-dependent process. We also found that TrkB-ICD has tyrosine kinase activity, inducing the phosphorylation of nuclear and axonal proteins.
	These findings suggest that TrkB-ICD may lead to a dysregulation of the activity of several proteins, including proteins in the nucleus, to where TrkB-ICD migrates. Since TrkB-ICD is formed by Aβ peptide-induced cleavage of TrkB-FL, the present data highlights a new mechanism that may have a role in AD pathophysiology.