Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment

Kazuya Fukumoto; Hiroyuki Mizoguchi; Hideyuki Takeuchi; Hiroshi Horiuchi; Jun Kawanokuchi; Shijie Jin; Tetsuya Mizuno; Akio Suzumura

doi:10.1016/j.bbr.2014.03.046

Fingolimod increases brain-derived neurotrophic factor levels and ameliorates amyloid β-induced memory impairment

Behav Brain Res. 2014 Jul 15:268:88-93. doi: 10.1016/j.bbr.2014.03.046. Epub 2014 Apr 5.

Authors

Kazuya Fukumoto¹, Hiroyuki Mizoguchi², Hideyuki Takeuchi³, Hiroshi Horiuchi³, Jun Kawanokuchi³, Shijie Jin³, Tetsuya Mizuno³, Akio Suzumura³

Affiliations

¹ Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
² Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Electronic address: h-mizo@riem.nagoya-u.ac.jp.
³ Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.

PMID: 24713151
DOI: 10.1016/j.bbr.2014.03.046

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder. Amyloid β, a neurotoxic protein, causes disruption of hippocampal synaptic plasticity, and induces cognitive impairment in Alzheimer's disease. We previously revealed that fingolimod, a new oral immunosuppressant used to treat multiple sclerosis, ameliorates oligomeric amyloid β-induced neuronal damage via up-regulation of neuronal brain-derived neurotrophic factor (BDNF). Here, we showed that oral administration of fingolimod ameliorated the impairment in object recognition memory and associative learning in mice injected with amyloid β. This effect was associated with restoration of normal BDNF expression levels in the cerebral cortices and hippocampi, suggesting that neuroprotection was mediated by up-regulation of neuronal BDNF levels. Therefore, fingolimod may provide therapeutic effects in patients with Alzheimer's disease.

Keywords: Alzheimer's disease; Amyloid β; Brain-derived neurotrophic factor; Fingolimod.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease
Amyloid beta-Peptides / toxicity*
Animals
Association Learning / drug effects
Association Learning / physiology
Brain / drug effects*
Brain / physiopathology
Brain-Derived Neurotrophic Factor / metabolism*
Cerebral Cortex / drug effects
Cerebral Cortex / physiopathology
Exploratory Behavior / drug effects
Exploratory Behavior / physiology
Fingolimod Hydrochloride
Hippocampus / drug effects
Hippocampus / physiopathology
Male
Memory Disorders / drug therapy*
Memory Disorders / etiology
Memory Disorders / physiopathology
Mice, Inbred C57BL
Neuroprotective Agents / pharmacology*
Peptide Fragments / toxicity*
Propylene Glycols / pharmacology*
Recognition, Psychology / drug effects
Recognition, Psychology / physiology
Sphingosine / analogs & derivatives*
Sphingosine / pharmacology
Up-Regulation

Substances

Amyloid beta-Peptides
Brain-Derived Neurotrophic Factor
Neuroprotective Agents
Peptide Fragments
Propylene Glycols
amyloid beta-protein (1-42)
Fingolimod Hydrochloride
Sphingosine