The amyloid hypothesis of Alzheimer's disease suggests that synaptic degeneration and pathology is caused by the accumulation of amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP). Subsequently, soluble Aβ oligomers cause the loss of synaptic proteins from neurons, a histopathological feature of Alzheimer's disease that correlates with the degree of dementia. In this study, the production of toxic forms of Aβ was examined in vitro using 7PA2 cells stably transfected with human APP. We show that conditioned media from 7PA2 cells containing Aβ oligomers caused synapse degeneration as measured by the loss of synaptic proteins, including synaptophysin and cysteine-string protein, from cultured neurons. Critically, conditioned media from 7PA2 cells treated with valproic acid (2-propylpentanoic acid (VPA)) or propylisopropylacetic acid (PIA) did not cause synapse damage. Treatment with VPA or PIA did not significantly affect total Aβ42 concentrations; rather these drugs selectively reduced the concentrations of Aβ42 oligomers in conditioned media. In contrast, treatment significantly increased the concentrations of Aβ42 monomers in conditioned media. VPA or PIA treatment reduced the concentrations of APP within lipid rafts, membrane compartments associated with Aβ production. These effects of VPA and PIA were reversed by the addition of platelet-activating factor, a bioactive phospholipid produced following activation of phospholipase A2, an enzyme sensitive to VPA and PIA. Collectively these data suggest that VPA and PIA reduce Aβ oligomers through inhibition of phospholipase A2 and suggest a novel therapeutic approach to Alzheimer's treatment.