Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques, cerebrovascular amyloid deposits, intracellular neurofibrillary tangles, and neuronal loss. Amyloid deposits are composed of insoluble fibers of a 39–43 amino acid peptide named the amyloid β-protein (Aβ). Neuropathological and genetic studies provide strong evidence of a key role for Aβ amyloidosis in the pathogenesis of AD. Therefore, an obvious pharmacological target for treatment of AD is the inhibition of amyloid growth and/or inhibition of amyloid function. We took an unbiased approach to generate new inhibitors of amyloid formation by screening a FliTrx™ combinatorial peptide library for Aβ binding peptides and identified four groups of peptides with different Aβ binding motifs. In addition, we designed and examined peptides mimicking the Aβ binding domain of transthyretin (TTR). Our results showed that Aβ binding peptides selected from FliTrx™ peptide library and from TTR-peptide analogs are capable of inhibiting Aβ aggregation and Aβ deposition in vitro. These properties demonstrate that binding of selected peptides to the amyloid β-protein may provide potent therapeutic compounds for the treatment AD.

Keywords:

• Alzheimer's disease
• amyloid beta protein
• transthyretin
• peptide library

Abbreviations
AD	=	Alzheimer's disease
TTR	=	transthyretin
FAD	=	Familial Alzheimer's disease
PBS	=	phosphate buffered saline
AβPP	=	amyloid beta-protein precursor
Aβ	=	amyloid-beta peptide

Abbreviations
AD	=	Alzheimer's disease
TTR	=	transthyretin
FAD	=	Familial Alzheimer's disease
PBS	=	phosphate buffered saline
AβPP	=	amyloid beta-protein precursor
Aβ	=	amyloid-beta peptide