Roles for dysfunctional sphingolipid metabolism in Alzheimer's disease neuropathogenesis

Abstract

Sphingolipids in the membranes of neurons play important roles in signal transduction, either by modulating the localization and activation of membrane-associated receptors or by acting as precursors of bioactive lipid mediators. Activation of cytokine and neurotrophic factor receptors coupled to sphingomyelinases results in the generation of ceramides and gangliosides, which in turn, modify the structural and functional plasticity of neurons. In aging and neurodegenerative conditions such as Alzheimer's disease (AD), there are increased membrane-associated oxidative stress and excessive production and accumulation of ceramides. Studies of brain tissue samples from human subjects, and of experimental models of the diseases, suggest that perturbed sphingomyelin metabolism is a pivotal event in the dysfunction and degeneration of neurons that occurs in AD and HIV dementia. Dietary and pharmacological interventions that target sphingolipid metabolism should be pursued for the prevention and treatment of neurodegenerative disorders.

Figure 1

Pathways of Sphingolipid Metabolism

Figure 2. Amyloid Processing in Lipid Rafts

Amyloid precursor protein (APP) cleavage by β- and γ-secretases occurs most efficiently in lipid rafts. Aβ binds to membranes with a preference for anonic lipid head groups and can be translocated into GM1-rich lipid rafts where Aβ undergos a conformational shift that disrupts membrane stability, promotes peptide-peptide interactions and Aβ oligomer formation.

Figure 3. Roles for Sphingolipids in the Regulation and Dysregulation of Synaptic Functions

Sphingosine can regulate neurotransmitter release by neutralizing interactions of snaptobrevin with phospholipids in synaptic vesicles. This action allows synaptobrevin to engage syntaxin/SNAP-25 on the inner leaflet of pre-synaptic membranes. A rapid and focal generation of ceramide by SMase promotes vesicle fusion with the plasma membrane and release of neurotransmitters. Sphingosine 1-phosphate (S1P) can signal in an autocrine manner through S1P receptors to further enhance the neurotransmitter release. At the post-synaptic terminal, rapid and transient increases of ceramide and DAG regulates plasma membrane trafficking of NMDA receptors by promoting the fusion of receptor-laden vesicles with the plasma membrane. In AD, disruptions of sphingolipid metabolism perturb these sphingolipid-regulated pre- and post-synaptic functions, and sustained increases of ceramide may activate ceramide associated protein kinases (CAPK) and protein phosphateases (CAPP) to promote death signaling in neurons.