The effect of different cholesterol levels in neuronal cells on amyloid beta toxicity and steroid synthesis

Amyloid beta(AB) toxicity is one of the initiator factors in neurodegeneration process.It hasbeen suggested that cholesterol induced synthesis of AB from amyloidprecursor protein or facilitated formation of amyloid-plaque by lowering aggregation threshold of peptide.On the other hand, it is also possible that AB may affect cholesterol metabolism and synthesis of cholesterolderivatives. Pregnenolone(P) and pregnenolonesulfate(PS) are major steroids produced from cholesterol in neuraltissue.P has protective effects against neuronaltoxicity,PS which is a memory modulator, can behave as natural excitotoxin in concentrations above1μM.At neurotoxicity conditions,effect of AB on synthesis of P/PS hasnot been clearly identified yet.The aim of study was to investigate possible relationship between cellular cholesterol,AB-toxicity and P/PSsynthesis. Three different AB(AB25-35/AB1-40/AB1-42) in toxicconcentration and cholesterol were applied to PC-12 and SHSY-5Ycells.The effects of applied AB and cholesterol on intracellular cholesterol,P/PS levels were determined.Viability and celldeath types were evaluated. AB applications for72hours have reduced viability level to50% of controlcells. Total cholesterol levels of cells were increased up to~5-6fold following cholesterol application for 24hours.Treatment withAB and increasing cholesterol caused significant decrease in cellviability.Concurrent application of AB with cholesterol increased Plevels more than group treated only with cholesterol.While all AB-fragments caused increase in Plevels,PS levels were changed according to fragment-type and cholesterol levels.Reduction of viability in group-treated both with AB and cholesterol canbe resolved with partial-inhibition of steroidogenesis. With thisstudy in-vitro data about relationship between cholesterol,P/PS and AB-toxicity hasbeen obtained.AB have changed both viability and neurosteroid levels depending on fragment-type and cholesterol levels.Consequently,it maybe suggested that cholesterol may play potential keyrole in AB-toxicity by affecting neurosteroid levels