Abstract
Alzheimer’s disease (AD), the most common cause of dementia remains of unclear etiology with current pharmacological therapies failing to halt disease progression. Several pathophysiological mechanisms have been implicated in AD pathogenesis including amyloid-β protein (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation and alterations in bioactive lipid metabolism. Sphingolipids, such as sphingosine-1-phosphate (S1P) and intracellular ceramide/S1P balance are highly implicated in central nervous system physiology as well as in AD pathogenesis. FTY720/Fingolimod, a structural sphingosine analog and S1P receptor (S1PR) modulator that is currently used in the treatment of relapsing–remitting multiple sclerosis (RRMS) has been shown to exert beneficial effects on AD progression. Recent in vitro and in vivo evidence indicate that fingolimod may suppress Aβ secretion and deposition, inhibit apoptosis and enhance brain-derived neurotrophic factor (BDNF) production. Furthermore, it regulates neuroinflammation, protects against N-methyl-d-aspartate (NMDA)-excitotoxicity and modulates receptor for advanced glycation end products signaling axis that is highly implicated in AD pathogenesis. This review discusses the underlying molecular mechanisms of the emerging neuroprotective role of fingolimod in AD and its therapeutic potential, aiming to shed more light on AD pathogenesis as well as direct future treatment strategies.
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Abbreviations
- Aβ:
-
Amyloid-β protein
- AChEI:
-
Acetylcholinesterase inhibitors
- AD:
-
Alzheimer’s disease
- AGEs:
-
Advanced glycation end products
- APP:
-
Aβ precursor protein
- AV:
-
Atrioventricular
- BACE1:
-
β-Site APP cleaving enzyme-1
- BAFF:
-
B-cell activating factor
- BBB:
-
Blood–brain barrier
- BCL-2:
-
B-cell lymphoma 2
- BDNF:
-
Brain-derived neurotrophic factor
- BMECs:
-
Brain microvascular endothelial cells
- CERK:
-
Ceramide kinase
- CNS:
-
Central nervous system
- COX-II:
-
Cyclooxygenase-II CXCL10: C-X-C motif chemokine 10 protein
- EAE:
-
Autoimmune encephalomyelitis
- GPCR:
-
G-protein-coupled receptor
- HBEGF:
-
Heparin-binding EGF-like growth factor
- FPRL1:
-
Formyl peptide receptor like-1
- HMGB1:
-
High-mobility group box 1
- IRF-3:
-
Interferon regulatory factor 3
- JNK-I:
-
c-Jun N-terminal kinase-I
- LIF:
-
Leukemia-inhibitory factor
- LTP:
-
Long-term potentiation
- MWM:
-
Morris water maze
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- NMDA:
-
N-methyl-d-aspartate
- RAGE:
-
Receptor for advanced glycation end products
- MS:
-
Multiple sclerosis
- RRMS:
-
Relapsing–remitting multiple sclerosis
- S1P:
-
Sphingosine-1-phosphate
- S1PR:
-
S1P receptor
- SphK:
-
Sphingosine kinase
- STAT3:
-
Signal transducer and activator of transcription 3
- TNF-α:
-
Tumor necrosis factor-α
- TrKB:
-
Tropomyosin-related kinase B
- VCAM-1:
-
Vascular cell adhesion molecule-1
- VEGFD:
-
Vascular endothelial growth factor D
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Angelopoulou, E., Piperi, C. Beneficial Effects of Fingolimod in Alzheimer’s Disease: Molecular Mechanisms and Therapeutic Potential. Neuromol Med 21, 227–238 (2019). https://doi.org/10.1007/s12017-019-08558-2
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DOI: https://doi.org/10.1007/s12017-019-08558-2