Year: 2012
Type: article
Abstract: The tyrosine kinase receptor B (TrkB) is the receptor for brain derived neurotrophic factor (BDNF). Its signaling and regulation is important for neuronal function, synaptic plasticity and long-term potentiation. There are three different isoforms of TrkB in humans: one is catalytically active, TrkB FL, and two are not: TrkB T and TrkB SHC. Experimental evidence suggests that they differentially affect APP cleavage and contribute to memory impairment in animal models of Alzheimer's disease (AD). APP cleavage is a fundamental event in AD and it is mediated by several proteolytic enzymes. Two of these, ADAM10 and BACE1, mediate the non-amyloidogenic and the amyloidogenic cleavages of APP respectively. TrkB FL has been shown to increase the non-amyloidogenic cleavage of APP. We hypothesized that TrkB isoforms can alter APP levels and ADAM10/BACE1 levels or activity and therefore contribute to the pathology of AD. We tested our hypothesis by over-expressing the different isoforms of the receptor and some point mutants in two different human cell lines: HEK293 and SH-SY5Y cells. We then measured endogenous levels of APP, BACE1 and ADAM10. We also measured ADAM10 activity. Finally we employed a luciferase reporter assay to test TrkB FL mediated transcriptional activation. We found that TrkB FL increased APP endogenous levels in both human cell lines while TrkB T did not alter these levels. Surprisingly, we did not find a significant difference in ADAM10 activity but an increase in BACE1 levels when over-expressing the TrkB FL receptor. This was not observed with the truncated counterparts or when mutating the SHC binding site of the TrkB FL receptor. We also found that NFAT3 activation mediated by TrkB FL signaling might explain the increase in BACE1 levels. We conclude that TrkB isoforms are involved in AD molecular mechanisms by directly affecting endogenous APP and BACE1 levels. TrkB FL increases BACE1 levels in vitro and this effect is SHC mediated. All these mechanisms need to be better elucidated before implementing successful BDNF based therapies for AD.
Source: Alzheimer s & Dementia
Authors: Sara Ansaloni, Brian Leung, Aleister Saunders
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2110344596