Fingolimod modulates multiple neuroinflammatory markers in a mouse model of Alzheimer's disease.
Sphingosine 1-phosphate (SP1) receptors may be attractive targets for modulation of inflammatory processes in neurodegenerative diseases. Recently fingolimod, a functional S1P1 receptor antagonist, was introduced for treatment of multiple sclerosis. We postulated that anti-inflammatory mechanisms of fingolimod might also be protective in Alzheimer's disease (AD). Therefore, we treated a mouse model of AD, the 5xFAD model, with two doses of fingolimod (1 and 5 mg/kg/day) and measured the response of numerous markers of Aβ pathology as well as inflammatory markers and neurochemistry using biochemical, immunohistochemistry and high resolution magic angle spinning magnetic resonance spectroscopy (MRS). In mice at 3 months of age, we found that fingolimod decreased plaque density as well as soluble plus insoluble Aβ measured by ELISA. Fingolimod also decreased GFAP staining and the number of activated microglia. Taurine has been demonstrated to play a role as an endogenous anti-inflammatory molecule. Taurine levels, measured using MRS, showed a very strong inverse correlation with GFAP levels and ELISA measurements of Aβ, but not with plaque density or activated microglia levels. MRS also showed an effect of fingolimod on glutamate levels. Fingolimod at 1 mg/kg/day provided better neuroprotection than 5 mg/kg/day. Together, these data suggest a potential therapeutic role for fingolimod in AD.
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA.|Department of Neurology Boston University School of Medicine, Boston, MA 02118, USA.|A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Nurgul
N
Aytan
A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Ji-Kyung
JK
Choi
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA.|Department of Biochemistry Boston University School of Medicine, Boston, MA 02118, USA.
Isabel
I
Carreras
Development Franchise Neuroscience, Novartis Pharma AGNovartis CampusFabrikstrasse 12CH-4056 Basel, Switzerland.
Volker
V
Brinkmann
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA.|Department of Neurology Boston University School of Medicine, Boston, MA 02118, USA.
Neil W
NW
Kowall
A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Bruce G
BG
Jenkins
Department of Veterans Affairs, VA Boston Healthcare System, Boston, MA 02130, USA.|Department of Neurology Boston University School of Medicine, Boston, MA 02118, USA.|A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Alpaslan
A
Dedeoglu
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000032:analysis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage*; D051379:Mice; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D000068876:Fingolimod Hydrochloride