Alzheimer’s disease can be viewed as a protein misfolding disease. Inappropriate processing of the proteolytic fragment of amyloid precursor protein, amyloid β-protein (Aβ), in early stages of the disease may lead to the release of stable small oligomers that are highly mobile with the potential to be more toxic than larger fibrillar assemblies. Recently, the importance of such soluble species of Aβ in triggering synaptic dysfunction, long before neuronal loss occurs, has become apparent. Animal models have revealed that plasticity of hippocampal excitatory synaptic transmission is relatively selectively vulnerable to Aβ both in vitro and in vivo. This presentation focuses on the mechanisms of Aβ inhibition of long-term potentiation (LTP) at synapses in the rodent hippocampus from two complimentary perspectives. First, we will examine evidence that the synaptic plasticity disrupting effect of this peptide resides primarily in oligomeric rather than monomeric or fibrillar Aβ species. Cell-derived Aβ oligomers can be purified with size-exclusion chromatography and shown to inhibit LTP at subnanomolar concentrations. Exogenously applied and endogenously generated antibodies that can avidly bind Aβ oligomers can protect against the inhibition of LTP by directly neutralizing them in the brain. Second, the importance of different oxidative/nitrosative stress-linked cascades including JNK, p38 MAPK and NADPH oxidase/iNOS-generated reactive oxygen/nitrogen free radicals in mediating the inhibition of LTP by Aβ will be evaluated. Selective inhibitors of these cascades can abrogate the inhibition of LTP by Aβ. Remarkably, agents that reduce the levels of the cytokine Tumor Necrosis Factor (TNF)α are also protective and mice deficient in type 1 TNF receptors are resistant to the inhibion of LTP by Aβ. Such mechanistic studies provide a plausible explanation for the sensitivity of hippocampus-dependent memory to impairment in early Alzheimer’s disease patients. Mechanism-based therapeutic strategies targeting Aβ oligomers and pro-inflammatory synaptic stress provide an attractive strategy in the control of early Alzheimer’s disease.