Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood-Brain Barrier

One of the treatment strategies for Alzheimer's disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (A beta) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35-38 region of the alpha 4 subunit of alpha 4 beta 2 nicotinic acetylcholine receptor and specifically binds to the 11-14 site of A beta, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood-brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with A beta species directly in the brain.

Automated summary

The study showed that HAEE can cross the blood-brain barrier and interact directly with A beta, reducing cerebral amyloidogenesis in a mouse model of AD. This anti-amyloid effect is likely due to the interaction between HAEE and A beta species in the brain.