Person:

Tanzi, Rudolph

Background: The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings: Here, we provide data supporting an in vivo function for Aβ as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Aβ and LL-37, an archetypical human AMP. Findings reveal that Aβ exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. Conclusions/Significance: Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies.

Background: The amyloid (\beta)-protein (A(\beta)) is believed to be the key mediator of Alzheimer's disease (AD) pathology. A(\beta) is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, A(\beta) has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings: Here, we provide data supporting an in vivo function for A(\beta) as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of A(\beta) and LL-37, an archetypical human AMP. Findings reveal that A(\beta) exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue A(\beta) levels. Consistent with A(\beta)-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-A(\beta) antibodies. Conclusions/Significance: Our findings suggest A(\beta) is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of A(\beta)-mediated pathology and has important implications for ongoing and future AD treatment strategies.