Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Abeta(1-42).

Alzheimer's disease is characterised by the loss of neurons and the production of Abeta peptides. We report that the addition of Abeta(1-42) to neurons resulted in activation of cytoplasmic phospholipase A(2) (cPLA(2)), the production of prostaglandin E(2), synapse damage and reduced neuronal survival. Pre-treatment with simvastatin, a clinically relevant statin that penetrates the brain, protected against Abeta(1-42) induced synapse damage and neuronal death in vitro. The neuroprotective effects of simvastatin were shared by squalestatin, a squalene synthase inhibitor that reduces neuronal cholesterol production and crucially, does not affect isoprenoid formation. The protective effect of both these drugs was reversed by the addition of exogenous cholesterol. These drugs did not alter the amounts of extracellular Abeta(1-42) ingested by neurons; rather they reduced Abeta(1-42) induced activation of cPLA(2) and prostaglandin E(2) production. Treatment prevented the migration of Abeta(1-42) and cPLA(2) to caveolin-1 containing lipid rafts. We propose that critical concentrations of Abeta(1-42) trigger the amalgamation of individual micro-domains containing signalling molecules to form lipid raft platforms in which sustained activation of cPLA(2) leads to neuronal dysfunction and ultimately neuronal death. This process is dependent on the amounts of cholesterol in neuronal membranes and is susceptible to treatment with squalestatin or simvastatin.