The loss of synapses and a corresponding reduction in synaptic proteins are histopathological features of Alzheimer's disease that correlate strongly with dementia. Here we report that stable Aβ oligomers secreted by 7PA2 cells reduced the amount of synaptophysin, a protein used as an indicator of synapse density, in cultured cortical and hippocampal neurons. Pre-treatment with physiologically relevant concentrations of ethanol (0.02-0.08%) protected neurons against Aβ-induced synapse damage. Ethanol also protected neurons against synapse damage induced by α-synuclein (αSN), pre-synaptic aggregates of which are characteristic of Parkinson's disease and dementia with Lewy bodies. Exposure of neurons to ethanol did not affect the accumulation of Aβ at synapses, rather it reduced the Aβ and αSN-induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) within synapses. Ethanol did not affect synapse damage caused by platelet-activating factor or prostaglandin E(2), bioactive lipids that are formed following the activation of cPLA(2). These results may help explain epidemiological reports that moderate alcohol consumption protects against the development of dementia in Alzheimer's and Parkinson's diseases.

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