The underlying cause of Alzheimer’s disease (AD) is thought to be the -amyloid aggregates formed mainly by A1-42 peptide. Protective pentapeptides (e.g., LPFFD) have been shown to prevent neuronal toxicity of A1-42 by arresting and reversing fibril formation. Here we report that an endogenous tetrapeptide, endomorphin-2 (End-2, amino acid sequence: YPFF) defends against A1-42 induced neuromodulatory effects at cellular concentration. Although End-2 does not interfere with the kinetics of A fibrillogenesis according to transmission electron microscopic studies and quasielastic light scattering measurements, it binds to A1-42 during aggregation, as revealed by tritium labeled End-2 binding assay and circular dichroism measurements. The tetrapeptide attenuates the inhibitory effect on cellular redox activity of A1-42 in a dose-dependent manner, as measured by MTT assay. In vitro and in vivo electrophysiological experiments show that End-2 also protects against the field excitatory postsynaptic potential (fEPSP) attenuating and the NMDA-evoked response-enhancing effect of A1-42. Studies using DAMGO, a µ-opioid receptor agonist, show that the protective effects of the tetrapeptide are not µ-receptor modulated. The endogenous tetrapeptide End-2 may serve as a lead compound for the drug development in the treatment of AD.