Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease, characterized by progressive memory loss and irreversible cognitive decline
Quantitative analyses of the amyloid beta plaques in frontal cortex shows that both dose of fingolimod treatment resulted in significant decreases in amyloid β (Aβ) 42 plaque deposition compared with mice given standard drinking water, the decrease in Aβ 40 plaque load did not reach significance with either dose of fingolimod treatment (Fig. 1b)
We found that the levels of total Aβ 42 and Aβ 40 were statistically lower in 1 mg/kg/day fingolimod-treated group compared to untreated-5xFAD group after 2 months of treatment
Summary
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease, characterized by progressive memory loss and irreversible cognitive decline. Aβ neurotoxicity is established to be a critical event in AD pathogenesis and correlated with neuronal and synapse loss, which causes synaptic failure resulting in cognitive dysfunction[2,3,4]. These events are accompanied by a progressive neuroinflammatory reaction involving the activation of microglia and astrocytes around amyloid plaques in AD pathology[5,6,7,8].
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