Amyloid-? peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.

ABSTRACT: Passive immunization with anti-amyloid-? peptide (A?) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of A?-specific DARPins. We further showed their ability to delay A? aggregation and prevent A?-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent A?-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble A? levels. These findings demonstrate the therapeutic potential of A?-specific DARPins for the treatment of Alzheimer disease.

SUBMITTER: Hanenberg M 

PROVIDER: S-EPMC4175345 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature