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Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
Sphingosine 1-phosphate attenuates neuronal dysfunction induced by amyloid-β oligomers through endocytic
Alessandra Bigi1, Roberta Cascella1, Giulia Fani1
1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy.
Abstract:
Soluble oligomers arising from the aggregation of the amyloid beta peptide (Aβ) have been identified as the main pathogenic agents in Alzheimer's disease (AD). Prefibrillar oligomers of the 42-residue form of Aβ (Aβ42 O) show membrane-binding capacity and trigger the disruption of Ca2+ homeostasis, a causative event in neuron degeneration. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the involvement of sphingosine 1-phosphate (S1P) signalling pathway in Ca2+ homeostasis in living neurons exposed to Aβ42 O. We show that both exogenous and endogenous S1P rescued neuronal Ca2+ dyshomeostasis induced by toxic Aβ42 O in primary rat cortical neurons and human neuroblastoma SH-SY5Y cells. Further analysis revealed a strong neuroprotective effect of S1P1 and S1P4 receptors, and to a lower extent of S1P3 and S1P5 receptors, which activate the Gi -dependent signalling pathways, thus resulting in the endocytic internalization of the extrasynaptic GluN2B-containing N-methyl-D-aspartate receptors (NMDARs). Notably, the S1P beneficial effect can be sustained over time by sphingosine kinase-1 overexpression, thus counteracting the down-regulation of the S1P signalling induced by Aβ42 O. Our findings disclose underlying mechanisms of S1P neuronal protection against harmful Aβ42 O, suggesting that S1P and its signalling axis can be considered promising targets for therapeutic approaches for AD.
Insights
Sphingosine 1-phosphate (S1P) protects neurons from amyloid beta (Aβ) oligomers, restoring calcium homeostasis. This pathway, involving S1P receptors and Gᵢ signaling, offers a potential therapeutic target for Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Amyloid beta (Aβ) oligomers are key pathogenic agents in Alzheimer's disease (AD), causing neuron degeneration by disrupting calcium (Ca²⁺) homeostasis.
- Bioactive lipids are emerging as potential protective agents against Aβ toxicity.
Purpose of the Study:
- To investigate the role of the sphingosine 1-phosphate (S1P) signaling pathway in maintaining Ca²⁺ homeostasis in neurons exposed to toxic Aβ oligomers.
- To explore S1P's neuroprotective mechanisms against Aβ-induced neuronal damage.
Main Methods:
- Primary rat cortical neurons and human neuroblastoma SH-SY5Y cells were used to study Aβ₄₂ oligomer toxicity.
- The effects of exogenous and endogenous S1P on Ca²⁺ homeostasis were assessed.
- The involvement of specific S1P receptors (S1P₁, S1P₃, S1P₄, S1P₅) and Gᵢ-dependent pathways was investigated.
- The impact of sphingosine kinase-1 overexpression on S1P signaling was examined.
Main Results:
- Both exogenous and endogenous S1P effectively rescued neuronal Ca²⁺ dyshomeostasis caused by Aβ₄₂ oligomers.
- S1P₁, S1P₄, and to a lesser extent S1P₃ and S1P₅ receptors mediated neuroprotection via Gᵢ-dependent pathways.
- Activation of these pathways led to the endocytic internalization of extrasynaptic GluN2B-containing N-methyl-D-aspartate receptors (NMDARs).
- Overexpression of sphingosine kinase-1 sustained S1P's beneficial effects by counteracting Aβ-induced downregulation of S1P signaling.
Conclusions:
- The S1P signaling axis plays a crucial role in protecting neurons against the toxic effects of Aβ₄₂ oligomers.
- S1P-mediated neuroprotection involves the modulation of Ca²⁺ homeostasis through specific receptor activation and NMDAR internalization.
- The S1P pathway represents a promising therapeutic target for Alzheimer's disease treatment.
