Publication
Title
Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing up-regulation and astrocyte-mediated inflammation
Author
Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by motor and cognitive impairments, involving striatum, cortex and hippocampus. Synaptic and memory dysfunction in HD mouse models have been related to low levels of brain-derived neurotrophic factor (BDNF) and imbalance between TrkB and p75NTR receptors. In addition, astrocyte over-activation has also been suggested to contribute to HD cognitive deficits. Fingolimod (FTY720), a modulator of sphingosine-1 phosphate (S1P) receptors, has been shown to increase BDNF levels and to reduce astrogliosis, proving its potential to regulate trophic support and inflammatory response. In this view, we have investigated whether FTY720 improves synaptic plasticity and memory in the R6/1 mouse model of HD, through regulation of BDNF signaling and astroglial reactivity. Chronic administration of FTY720 from pre-symptomatic stages ameliorated long-term memory deficits and dendritic spine loss in CA1 hippocampal neurons from R6/1 mice. Furthermore, FTY720 delivery prevented astrogliosis and over-activation of nuclear factor kappa beta (NF-κB) signaling in the R6/1 hippocampus, reducing tumor necrosis factor alpha (TNFα) and induced nitric oxide synthase (iNOS) levels. TNFα decrease correlated with the normalization of p75NTR expression in the hippocampus of FTY720-treated R6/1 mice, thus preventing p75NTR/TrkB imbalance. In addition, FTY720 increased cAMP levels and promoted phosphorylation of CREB and RhoA in the hippocampus of R6/1 mice, further supporting its role in the enhancement of synaptic plasticity. Our findings provide new insights into the mechanism of action of FTY720 and reveal a novel therapeutic strategy to treat memory deficits in HD.
Language
English
Source (journal)
Human molecular genetics. - Oxford
Publication
Oxford : 2015
ISSN
0964-6906
Volume/pages
24 :17 (2015) , p. 4958-4970
ISI
000361316300014
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Publication type
Subject
External links
Web of Science
Record
Identification
Creation 10.10.2018
Last edited 16.09.2021