Amyloid Beta (Aβ) peptide incompatibility with fibrinogen Results in Alzheimer’s disease

Alzheimer’s disease (AD) is a prevalent progressive neurodegenerative disorder, yet with undefinedorigin. The mostly accepted mechanism for AD pathogenesis is the Aβ hypothesis, stating that increasedgeneration of Amyloid-β protein is responsible for the senile plaques and dementia associated with AD[1]. A milestone in study of AD etiology is the recent discovery that Aβ associates with fibrinogen andinduces alterations in the structure of the fibrin clot, making it resistant to fibrinolysis [2].Designinginhibitory molecules against the interaction of Aβ with fibrinogen could be a promising approach tonormalize any blood clots formed in the brain and increase their lysis. Researchers have also designed aninhibitory molecule (RU505) to suppress the proposed Aβ-fibrinogen interaction. However, the molecularmechanisms of both pathogenic Aβ-fibrinogen association and therapeutic Aβ-RU505 interaction haveremained unknown [3].The present study employs molecular modeling and design methods to investigatethe Aβ interactions contributing to AD progress or its treatment.These tasks are what intended by thepresent study, where a more potent Aβ inhibitor (T-777) is introduced. We then propose a descriptivemodel of the association between Aβ and fibrinogen, plus a mechanistic model for the inhibitory bindingof RU505 and T-777 drug candidates.We found that most of the contacts between the Amyloid-β andfibrinogen are of the hydrogen bonding and hydrophobic nature. Though less frequent, the electrostaticcontacts showed specific patterns on both molecules, which give implications for future drug designstudies.

کلیدواژه ها:

Alzheimer’s disease (AD) ، Amyloid-β ، Fibrinogen ، AD drug