Filamentous Bacteriophage as a Novel Therapeutic Tool for Alzheimer's Disease Treatment

Abstract

Antibodies towards the N-terminal region of the amyloid-β peptide (AβP) bind to Aβ fibrils, leading to their disaggregation. We developed an immunization procedure using filamentous phages displaying the only four amino acids EFRH encompassing amino acids 3–6 of the 42 residues of AβP, found to be the main regulatory site for Aβ formation. Phages displaying EFRH epitope are effective in eliciting humoral response against AβP which, in turn, relieves amyloid burden in brains of amyloid-β protein precursor transgenic mice, improving their ability to perform cognitive tasks. In order to overcome the low permeability of the blood brain barrier for targeting ‘anti-aggregating’ monoclonal antibodies (mAbs) to Aβ plaques in the brain, we applied antibody engineering methods to minimize the size of mAbs while maintaining their biological activity. Single-chain antibodies displayed on the surface of filamentous phage showed the ability to enter the central nervous system (CNS). The genetically engineered filamentous bacteriophage proved to be an efficient, nontoxic viral delivery vector to the brain, offering an obvious advantage over other mammalian vectors. The feasibility of these novel strategies for production and targeting of anti-aggregating antibodies against Aβ plaques to disease affected regions in the CNS may have clinical potential for treatment of Alzheimer's disease.