Small molecule inhibitors of Abeta assembly

Abstract

The Aβ peptide assembles into a variety of distinct types of structures in vitro and in the brain which have different biological consequences. Differential effects of inhibitory small molecules suggest that a sequential monomer – oligomer – fibril mechanism is overly simplistic and that soluble toxic oligomers and fibrils can be formed in common or separate pathways depending on the local environment. As a result, the effects of inhibitors are often assay-dependent because multiple pathways are operating. This review discusses strategies for teasing apart the intricate protein–protein interactions that result in Aβ assembly.

Keywords:

• Oligomer
• fibril nucleation
• fibril extension
• toxicity

Abbreviations
ADDLs	=	Alzheimer Disease Diffusible Ligands;
AFM	=	atomic force microscopy;
βAPP	=	amyloid precursor protein;
ELISA	=	enzyme-linked immunosorbent assay;
EM	=	electron microscopy;
GAG	=	glycosaminoglycan;
IAPP	=	islet amyloid polypeptide;
PS1	=	presenilin-1;
SAR	=	structure activity relationship

Abbreviations
ADDLs	=	Alzheimer Disease Diffusible Ligands;
AFM	=	atomic force microscopy;
βAPP	=	amyloid precursor protein;
ELISA	=	enzyme-linked immunosorbent assay;
EM	=	electron microscopy;
GAG	=	glycosaminoglycan;
IAPP	=	islet amyloid polypeptide;
PS1	=	presenilin-1;
SAR	=	structure activity relationship