Affiliations: [a] Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| [b] Department of Psychology, The Ohio State University, Columbus, OH, USA
| [c] Discipline of Psychology, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
Correspondence:
[*]
Correspondence to: Stephen R. Robinson, Discipline of Psychology, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia. Tel.: +613 9925 7120; E-mail: stephen.robinson@rmit.edu.au.
Abstract: The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer’s disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.
