Abstract
Cognitive abilities are largely dependent on activation of cerebral tropomyosin-related kinase B receptors (TrkB) by brain-derived neurotrophic factor (BDNF) that is secreted under a bioactive form by both neurons and endothelial cells. In addition, there is mounting evidence for a link between endothelial function and cognition even though the underlying mechanisms are not well known. Therefore, we investigated the cerebral BDNF pathway, either neuronal or endothelial, in rheumatoid arthritis (RA) that combines both endothelial dysfunction (ED) and impaired cognition. Adjuvant-induced arthritis (AIA) in rats was used as a model of RA. Clinical inflammatory symptoms were evaluated from an arthritis score and brains were collected at day 31 ± 2 post-immunization. Neuronal expression of BDNF and TrkB phosphorylated at tyrosine 816 (p-TrkB) was examined in brain slices. Endothelial BDNF and p-TrkB expression was examined on both brain slices (hippocampal arterioles) and isolated cerebral microvessels-enriched fractions (vessels downstream to arterioles). The connection between endothelial nitric oxide (NO) and BDNF production was explored on the cerebrovascular fractions using endothelial NO synthase (eNOS) levels as a marker of NO production, Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) as a NOS inhibitor and glyceryl-trinitrate as a slow releasing NO donor. Brain slices displayed lower BDNF and p-TrkB staining in both neurons and arteriolar endothelial cells in AIA than in control rats. For endothelial cells but not neurons, a strong correlation was observed between BDNF and p-TrkB staining. Of note, a strong correlation was also observed between neuronal p-TrkB and endothelial BDNF staining. In cerebral microvessels-enriched fractions, AIA led to decreased BDNF and eNOS levels with a positive association between the 2 parameters. These effects coincided with decreased BDNF and p-TrkB staining in endothelial cells. The exposure of AIA cerebrovascular fractions to GTN increased BDNF levels while the exposure of control fractions to L-NAME decreased BDNF levels. Changes in the cerebral BDNF pathway were not associated with arthritis score. The present study reveals that AIA impairs the endothelial and neuronal BDNF/TrkB pathway, irrespective of the severity of inflammatory symptoms but dependent on endothelial NO production. These results open new perspectives for the understanding of the link between ED and impaired cognition.
Highlights
Brain-derived neurotrophic factor (BDNF) is present in high concentrations in the adult brain where it plays a crucial role in neuroplasticity, neurogenesis and angiogenesis (Pencea et al, 2001; Kim et al, 2004; Lu et al, 2014) through the phosphorylation of its cognate TrkB receptors at tyrosine 816 (p-TrkB) (Bathina and Das, 2015)
The main results of the present study are that (i) adjuvant-induced arthritis (AIA) alters the cerebral BDNF/TrkB pathway at both the endothelial and neuronal levels, (ii) activation of neuronal TrkB receptors correlated with endothelial BDNF expression, (iii) a connection exists between the endothelial BDNF/TrkB pathway and the capacity of the cerebral endothelium to produce NO, (iv) AIA-induced changes in either the cerebral BDNF pathway or endothelial NO production did not proportionate with the severity of inflammatory symptoms
The impairment of the cerebral BDNF pathway is largely involved in impaired cognition associated in animal models of psychiatric, neurologic and neurodegenerative diseases
Summary
Brain-derived neurotrophic factor (BDNF) is present in high concentrations in the adult brain where it plays a crucial role in neuroplasticity, neurogenesis and angiogenesis (Pencea et al, 2001; Kim et al, 2004; Lu et al, 2014) through the phosphorylation of its cognate TrkB (tropomyosin-related kinase B) receptors at tyrosine 816 (p-TrkB) (Bathina and Das, 2015). In opposition with this traditional thinking, we recently showed that the removal of endothelial cells from the brain resulted in a marked decrease in BDNF levels measured in the cerebral tissue (Monnier et al, 2017b) This shift of paradigm in the cellular origin of cerebral BDNF indicates that a hitherto unexpected large part of BDNF found in the brain corresponds to BDNF produced by cerebral endothelial cells and paves the way for the exciting hypothesis that neuronal function might be dependent on neuronal-derived BDNF and on BDNF secreted by endothelial cells of cerebral capillaries. The potential connection between the cerebral BDNF pathway with the severity of inflammatory symptoms or endothelial NO production was investigated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
