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PRFF Peptide Mimic Interferes with Toxic Fibrin-Aβ42 Interaction by Emulating the Aβ Binding Interface on Fibrinogen
Sayan Bhattacharjee1, Rajanya Bhattacharyya1
1Structural Biology & Bio-Informatics Division, CSIR - Indian Institute of Chemical Biology, Kolkata 700032, India.
Abstract:
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.
Insights
A novel peptide inhibits toxic interactions between fibrinogen and amyloid-beta 42, offering a potential therapeutic for Alzheimer's disease-associated cerebral amyloid angiopathy by dissolving abnormal blood clots.
Area of Science:
- Neuroscience
- Biochemistry
- Vascular Biology
Background:
- Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are prevalent in Alzheimer's disease (AD).
- Fibrinogen's interaction with amyloid-beta 42 (Aβ42) in the brain forms plasmin-resistant clots, contributing to AD pathology.
- Current therapeutic options for AD-associated CAA are limited.
Purpose of the Study:
- To identify a therapeutic agent targeting the fibrinogen-Aβ42 interaction in Alzheimer's disease.
- To investigate a peptide's ability to inhibit clot formation and dissolve existing abnormal clots.
- To explore a novel therapeutic strategy for cerebral amyloid angiopathy.
Main Methods:
- A 13-amino acid peptide (Pα-NPGRPEPGSAGTW) was designed and synthesized.
- The peptide's interaction with Aβ42 and fibrinogen was analyzed.
- The peptide's effect on fibrin-Aβ42 complex formation and clot dissolution was evaluated.
- The peptide's specificity for inhibiting toxic interactions without affecting normal fibrin polymerization was assessed.
Main Results:
- A peptide, Pα, was identified as a potential inhibitor of the toxic fibrinogen-Aβ42 interaction.
- Pα demonstrated the ability to dissolve pre-existing plasmin-resistant abnormal clots.
- The peptide shares partial sequence similarity with a known Aβ42-binding fibrinogen fragment (PRFF).
- Pα selectively inhibits the pathological fibrin-Aβ42 interaction while preserving normal fibrin polymerization.
Conclusions:
- The identified peptide Pα shows promise as a therapeutic agent for Alzheimer's disease-associated cerebral amyloid angiopathy.
- Pα acts by competitively inhibiting the interaction between fibrinogen and Aβ42, preventing toxic clot formation.
- This peptide represents a potential new avenue for treating cerebrovascular complications in Alzheimer's disease.
