Amyloid-beta peptides (Abeta) generated by proteolysis of the beta-amyloid 
precursor protein (APP) by beta- and gamma-secretases play an important role in 
the pathogenesis of Alzheimer's disease (AD). There is mounting evidence that 
the lipid matrix of neuronal cell membranes plays an important role in the 
accumulation of Abeta peptides into senile plaques, one of the hallmarks of AD. 
With the aim to clarify the molecular basis of the interaction between Abeta and 
cellular membranes, we investigated the effects of various phospholipids (PLs) 
and a PL-rich diet on Abeta production. Here we show that modulation of Abeta 
production and Abeta42:40 ratio is not limited to individual fatty acids, rather 
it is the composition of the PLs of the membrane bilayer, that influences the 
specificity and level of the regulated intramembranous proteolysis of APP by the 
gamma-secretase complex. We show that Abeta levels in the conditioned media, in 
response to some of the PL supplements, is increased in the center and decreased 
on either side of a graph that resembles bell-shaped distribution. This means 
that the PLs have less of a tendency to produce unusually extreme effects on 
Abeta production in SP-C99 transfected Cos-7 cultured cells. We proposed a 
mechanism-based hypothesis to rationalize PLs' effects on Abeta production.