Frances Yen-Potin

Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-β peptide

Recent data have revealed that soluble oligomeric forms of amyloid peptide (Aβ) may be the proximate effectors of the neuronal injury and death occurring in Alzheimers disease (AD). However, the molecular mechanisms associated with the neuronal cell death induced by the nonfibrillar Aβ remain to be elucidated. In this study, we investigated the role of the cytosolic Ca2+‐dependent phospholipase A2 (cPLA2), and its associated metabolic pathway, i.e., the arachidonic acid (AA) cascade, in the apoptotic cell death induced by soluble oligomers of Aβ. The treatment of rat cortical neurons with low concentrations of soluble Aβ(1‐40) or Aβ(1‐42) peptide resulted in an early calcium‐dependent release of AA associated with a transient relocalization of cPLA2. Both cPLA2 antisense oligonucleotides and a selective inhibitor of cPLA2 activity abolished the release of AA from neurons and also protected cells against apoptosis induced by Aβ. Furthermore, inhibitors of the PKC, p38, and MEK/ERK pathways that are involved in cPLA2 phosphorylation and activation reduced Aβ‐induced cell death. Finally, we demonstrate that inhibitors of cyclooxygenase‐2 reduced the Aβ‐induced cell death by 55%. Our studies suggest a novel neuronal response of soluble oligomers of Aβ, which occurs through a cPLA2 signaling cascade and an AA‐dependent death pathway. This may prove to be crucial in AD processes and could provide important targets for drug development.

The essential role of lipids in Alzheimer's disease.

In the absence of efficient diagnostic and therapeutic tools, Alzheimers disease (AD) is a major public health concern due to longer life expectancy in the Western countries. Although the precise cause of AD is still unknown, soluble beta-amyloid (Abeta) oligomers are considered the proximate effectors of the synaptic injury and neuronal death occurring in the early stages of AD. Abeta oligomers may directly interact with the synaptic membrane, leading to impairment of synaptic functions and subsequent signalling pathways triggering neurodegeneration. Therefore, membrane structure and lipid status should be considered determinant factors in Abeta-oligomer-induced synaptic and cell injuries, and therefore AD progression. Numerous epidemiological studies have highlighted close relationships between AD incidence and dietary patterns. Among the nutritional factors involved, lipids significantly influence AD pathogenesis. It is likely that maintenance of adequate membrane lipid content could prevent the production of Abeta peptide as well as its deleterious effects upon its interaction with synaptic membrane, thereby protecting neurons from Abeta-induced neurodegeneration. As major constituents of neuronal lipids, n-3 polyunsaturated fatty acids are of particular interest in the prevention of AD valuable diet ingredients whose neuroprotective properties could be essential for designing preventive nutrition-based strategies. In this review, we discuss the functional relevance of neuronal membrane features with respect to susceptibility to Abeta oligomers and AD pathogenesis, as well as the prospective capacities of lipids to prevent or to delay the disease.