Propionyl-IIGL tetrapeptide antagonizes ß-amyloid excitotoxicity in rat nucleus basalis

A putative tetrapeptide β-amyloid (Aβ) antagonist (propionyl-Ile-Ile-Gly-Leu [Pr-IIGL]) based on the [31–34] sequence of Aβ was previously shown to rescue astrocytes from Aβ-induced membrane depolarization and subsequent long-term elevations of the intracellular Ca2+ concentration in vitro. Here we provide in vivo evidence that the Pr-IIGL tetrapeptide effectively attenuates the excitotoxic action of Aβ(1–42) on cholinergic neurons of the rat magnocellular nucleus basalis (MBN). We also demonstrate by means of microdialysis that administration of Pr-IIGL abolished Aβ(1–42)-induced increases in extracellular aspartate and glutamate concentrations in the MBN, which coincide with a significant preservation of cholinergic MBN neurons and their cortical projections. This neuroprotective effect was associated with preserved exploratory behavior in an open-field paradigm, and improved memory retention in a step-through passive avoidance task. Our data presented here indicate for the first time the efficacy of short, modified functional Aβ antagonists in ameliorating Aβ excitotoxicity in vivo