The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

Abstract

BackgroundThe 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 FindingsHere, 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/SignificanceOur 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.

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…For example, Ab may function as an antimicrobial peptide. 238 The largely extracellular localization of Ab is consistent with the FG hypothesis, because essentially the same logic and analogous physiological ramifications would apply to cognition-perturbing intracellular and extracellular protein fragments. It should be noted that the study that described the circadian and sleep-deprivation pattern of Ab expression 237 did not consider the possibility, proposed by the FG hypothesis, that such a pattern may be a manifestation of the far more general phenomenon in which a multitude of different protein fragments are generated in the brain during wakefulness and are, collectively, the molecular cause of sleep.…”

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

“…In this context, however, it should be noted that correlation between plasma A β 42 and hs‐CRP was not particularly strong, indicating that significantly larger number of samples are still needed to comprehensively validate this relationship. Nevertheless, this finding is utmost importance, considering that A β 42 has recently been suggested to participate in the defense response against pathogens, stress, and inflammatory conditions, in both the CNS and periphery 13, 14, 45, 46. Accordingly, decreased plasma hs‐CRP levels have been repeatedly reported among AD patients 47, 48, 49, 50.…”

Ocular Biomarkers for Early Detection of Alzheimer's Disease

“…For this reason Aβ has been suggested to have a dual damage response role in the brain, by sealing the vasculature reducing brain oxygen requirement and combating oxidative stress [12]. A recent study also demonstrated that Aβ has significant antimicrobial ability against clinically relevant organisms, introducing an interesting hypothesis that infection might have a role in some forms of AD [13]. Whatever the role of Aβ in the healthy body, a large number of in vitro and in vivo AD studies, particularly those of EOFAD, have shown that higher than normal Aβ levels cause oxidative stress in the brain, resulting in synaptic loss, cell membrane damage, inflammation and ultimately result in neuronal cell death [14][15].…”