Cross-Linked Amyloid β-Protein Oligomers: A Missing Link in Alzheimer's Disease Pathology?

Amyloid β-protein (Aβ) oligomers are broadly viewed as the proximate mediators of toxicity in Alzheimer's disease (AD). Recent studies, however, provide substantial evidence that Aβ is involved in protection and repair of the central nervous system whereby Aβ oligomer and subsequent fibril formation are integral to its normal antimicrobial and antiviral function. These developments raise a question of what exactly makes Aβ oligomers toxic in the context of AD. This Perspective describes a paradigm shift in the search for toxic Aβ oligomer species that involves oxidative-stress-induced stabilization of Aβ oligomers via cross-linking and reviews most recent research elucidating structural aspects of cross-linked Aβ oligomers and potential inhibition of their toxicity.