Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Aβ1–42

Alzheimer's disease is characterised by the loss of neurons and the production of Aβ peptides. We report that the addition of Aβ1–42 to neurons resulted in activation of cytoplasmic phospholipase A2 (cPLA2), the production of prostaglandin E2, synapse damage and reduced neuronal survival. Pre-treatment with simvastatin, a clinically relevant statin that penetrates the brain, protected against Aβ1–42 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 Aβ1–42 ingested by neurons; rather they reduced Aβ1–42 induced activation of cPLA2 and prostaglandin E2 production. Treatment prevented the migration of Aβ1–42 and cPLA2 to caveolin-1 containing lipid rafts. We propose that critical concentrations of Aβ1–42 trigger the amalgamation of individual micro-domains containing signalling molecules to form lipid raft platforms in which sustained activation of cPLA2 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.