Abstract
Brain derived neurotrophic factor (BDNF) levels and signaling via the tyrosine receptor kinase B (TrkB) have been shown to be altered in Alzheimer’s Disease. In addition, it has been reported that the isoforms of TrkB can differentially affect metabolism of amyloid precursor protein (APP). Conversely, Ab, a neurotoxic cleavage product of APP, has been shown to impair TrkB/ BDNF signaling. Therefore, we investigated whether the changes observed in APP metabolism were due to the isoform-specific effects of TrkB on either APP expression, and/or on the expression and activity of ADAM10 and BACE1. Since BDNF levels are decreased in AD, we focused on BDNF independent effects of the TrkB isoforms. We found that TrkB FL increases endogenous APP levels in both HEK293 and SH-SY5Y naive cells. We did not find an increase in ADAM10 activity in HEK293 cells, but an increase in BACE1 levels. Additionally, we have found that TrkB FL is able to increase NFAT3 mediated transcriptional activity and we suggest that this causes transcriptional activation of the BACE1 promoter.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease that mainly affects the elderly and causes memory impairment and cognitive deficits, leading to a dramatic reduction in quality of life
In conclusion we find that tyrosine kinase receptor B (TrkB) FL over-expression increases amyloid precursor protein (APP) levels even in absence of exogenous brain derived neurotrophic factor (BDNF), suggesting that auto-activation of the receptor can mediate APP transcription
We find that BACE1 levels are increased by TrkB FL auto-activation in HEK293 cells
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease that mainly affects the elderly and causes memory impairment and cognitive deficits, leading to a dramatic reduction in quality of life. Other therapeutic approaches are aimed at restoring signaling pathways that are defective in AD [2]. One such signaling defect is that of the tyrosine kinase receptor B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF) [4]. TrkB/BDNF are important factors for neuronal homeostasis [5] and enhancing their signaling in AD is accompanied by cognitive benefits [6]. BDNF mimetics may have therapeutic applications [7,8] The efficacy of these therapies will depend on the ability of these compounds to bind to the variety of TrkB receptor isoforms that are expressed in neurons and on activation of the downstream signaling pathways
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