Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs

Angiotensin IV (AngIV; Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6))-related peptides have emerged as potential antidementia agents. However, their development as practical therapeutic agents has been impeded by a combination of metabolic instability, poor blood-brain barrier permeability, and an incomplete understanding of their mechanism of action. This study establishes the core structure contained within norleucine(1)-angiotensin IV (Nle(1)-AngIV) that is required for its procognitive activity. Results indicated that Nle(1)-AngIV-derived peptides as small as tetra- and tripeptides are capable of reversing scopolamine-induced deficits in Morris water maze performance. This identification of the active core structure contained within Nle(1)-AngIV represents an initial step in the development of AngIV-based procognitive drugs. The second objective of the study was to clarify the general mechanism of action of these peptides by assessing their ability to affect changes in dendritic spines. A correlation was observed between a peptide's procognitive activity and its capacity to increase spine numbers and enlarge spine head size. These data suggest that the procognitive activity of these molecules is attributable to their ability to augment synaptic connectivity.