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.