Alzheimer's Amyloid-beta is an Antimicrobial Peptide: A Review of the Evidence

The amyloid-beta (A beta) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced A beta 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 A beta 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 A beta 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-beta protein precursor (A beta PP) and resultant fibrillary aggregates of A beta. Evidence from in vitro and in vivo studies demonstrates that A beta oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of A beta confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of A beta may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted A beta. 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.