PRFF Peptide Mimic Interferes with Toxic Fibrin-Aβ₄₂ Interaction by Emulating the Aβ Binding Interface on Fibrinogen

Cerebrovascular dysfunction is a common phenomenon in Alzheimer's patients, where fibrinogen is a major player. With the blood-brain barrier compromised, fibrinogen gains access to the brain, where its interaction with Aβ₄₂ results in plasmin-resistant abnormal blood clots that are deposited in the cerebral blood vessels, a condition commonly encountered in Alzheimer's disease (AD) patients called cerebral amyloid angiopathy (CAA). So far, there have been no effective therapeutics available to combat AD-associated CAA. This study reports a 13-amino acid peptide (Pα-NPGRPEPGSAGTW) as a potential inhibitor of the fibrin-Aβ₄₂ interaction along with the property to dissolve pre-existing plasmin-resistant abnormal clots. Strikingly, the identified sequence was found to be partially similar to a fragment of the fibrinogen α-chain reported to bind Aβ₄₂, the plasmin-resistant fibrinogen fragment (PRFF). Mechanistically, Pα interacts with Aβ₄₂ in place of fibrinogen, thus inhibiting the toxic fibrin-Aβ₄₂ interaction. However, it does not interfere with normal fibrin polymerization.