Toxic mechanisms of amyloid oligomers and therapeutic strategies

Amyloid oligomers are increasingly recognized as the major toxic contributors across protein-misfolding disorders. In this review, we cover mechanistic evidence showing how these transient and structurally heterogeneous oligomers disrupt cellular homeostasis by: (i) permeabilizing lipid membranes and forming ion-conducting pores; (ii) triggering endoplasmic reticulum (ER) stress and unfolded protein response (UPR), thereby compromising proteostasis via dysfunction of the ubiquitin-proteasome system (UPS) and autophagy; (iii) impairing mitochondrial function and disrupting redox balance; (iv) interfering with endosomal-lysosomal as well as axonal and synaptic trafficking; and (v) activating stress-kinase signaling and apoptotic pathways. In relation to therapeutic intervention, we review secretase-targeting strategies, conformation-selective antibodies, and their mixed clinical outcomes. An in-depth understanding of the toxic action of pathogenic oligomeric species will be critical for translating these mechanistic insights into effective therapies that comprehensively target oligomer toxicity.