The underlying cause of Alzheimer's disease (AD) is thought to be the accumulation and aggregation of a misfolded protein, amyloid-beta (Abeta). A promising strategy against AD is the application of protective, peptide-based neuroprotective agents that selectively bind to Abeta. We recently described a pentapeptide, LPYFDa, which recognizes Abeta (1-42) and protects neurons against the toxic effects of aggregated Abeta (1-42) both in vitro and in vivo. Our previous work indicated that the in vivo ejection of fibrillar Abeta (1-42) into the hippocampal CA1 region resulted in a massive increase in the NMDA-evoked neuronal firing rate. Our current aim was to study whether intraperitoneally administered LPYFDa is capable of protecting against the synaptotoxic action of fibrillar Abeta (1-42) administered by iontophoresis. Our investigations of the in vivo biodistribution of tritium-labelled LPYFDa and single-unit electrophysiology revealed that LPYFDa readily crosses the blood-brain barrier, and protects the synapses against the excitatory action of fibrillar Abeta (1-42) in a relatively wide temporal window in rat. This pentapeptide may serve as a lead compound for the design of novel drug candidates for the prevention of AD.