Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques

Abstract

Amyloid-beta (A beta) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-A beta drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood-brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-A beta peptidomimetics that exploit the self-assembling nature of A beta and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of A beta, DAB, found to cross the BBB and solubilize A beta oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-A beta interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.