Human molecular geneticsJun 12, 2015

Fingolimod improves memory and brain cell communication in Huntington's disease by stopping harmful protein increase and brain inflammation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 4, 2026

Abstract

Chronic administration of FTY720 improved long-term memory deficits and dendritic spine loss in CA1 hippocampal neurons in R6/1 mice.

FTY720 is associated with increased levels of brain-derived neurotrophic factor (BDNF) in the context of Huntington's disease.
Treatment with FTY720 prevented astrogliosis and reduced over-activation of nuclear factor kappa beta (NF-κB) signaling.
A decrease in tumor necrosis factor alpha (TNFα) correlated with normalized p75(NTR) expression in the hippocampus of treated R6/1 mice.
FTY720 administration increased cAMP levels and promoted phosphorylation of CREB and RhoA in the hippocampus.
These changes may enhance synaptic plasticity, suggesting a potential therapeutic strategy for memory deficits in Huntington's disease.

Simplified

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 p75(NTR) 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 p75(NTR) expression in the hippocampus of FTY720-treated R6/1 mice, thus preventing p75(NTR)/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.

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Fingolimod improves memory and brain cell communication in Huntington's disease by stopping harmful protein increase and brain inflammation

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