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

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

doi:10.3389/fnmol.2019.00004

João Fonseca-Gomes, Ana M Sebastião + Show 5 more

Open Access

https://doi.org/10.3389/fnmol.2019.00004

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Abstract

The signaling 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 tropomyosin-receptor kinase B-full-length (TrkB-FL) have been detected in human brain samples of AD patients. We have previously found that neuronal exposure to amyloid-β (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 signaling 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.

Highlights

Alzheimer’s disease (AD) is a slow progressing neurodegenerative disease, leading to atrophy and neuronal loss of particular brain regions, in particular the hippocampus, leading to cognitive impairments (Huang and Mucke, 2012)
The appropriate function of this signaling pathway is crucial for the central nervous system homeostasis, and its dysregulation might lead to neuronal damage
It is already known that an impaired brain-derived neurotrophic factor (BDNF)/full-length isoform of Tropomyosin-receptor kinase B (TrkB-FL) system plays an important role in the pathogenesis of AD (Phillips et al, 1991; Connor et al, 1997; Ferrer et al, 1999; Arancibia et al, 2008; Zuccato and Cattaneo, 2009; Kemppainen et al, 2012; Nagahara et al, 2013; Jerónimo-Santos et al, 2015)

Summary

INTRODUCTION

Alzheimer’s disease (AD) is a slow progressing neurodegenerative disease, leading to atrophy and neuronal loss of particular brain regions, in particular the hippocampus, leading to cognitive impairments (Huang and Mucke, 2012). As we recently found in cell cultures, Aβ peptide, through extrasynaptic NMDA receptors, promotes the increase of intracellular calcium levels, leading to the overactivation of calpains, which promote TrkB-FL cleavage (Jerónimo-Santos et al, 2015; Tanqueiro et al, 2018) This process leads to the decrease of TrkB-FL levels and the generation of two distinct fragments: a membrane-bound truncated receptor (TrkB-T ) and an intracellular fragment (TrkB-ICD). We found that TrkB-ICD is a stable fragment, which, over time, translocates into nucleus and phosphorylates nuclear and axonal proteins Taken together, these data strongly suggest that TrkB-FL cleavage could be an important step of AD pathophysiology, since it leads to a loss of BDNF signaling and forms an intracellular fragment that might propagate Aβ toxicity to the neurons

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