Amyloid-β Peptide Protects Against Microbial Infection In Mouse and Worm Models of Alzheimer’s Disease

By Deepak K Vijaya Kumar, Se Hoon Choi, Kevin J. Washicosky, William A. Eimer, S. Tucker, Jessica Ghofrani, Aaron Lefkowitz, Gawain McColl, L. Goldstein, Rudolph E. Tanzi and 1 more. Science Translational Medicine, 2016

859 citations recorded by the source corpus.

β-Amyloid protein oligomerization and fibrillization, known to be pathogenic in Alzheimer’s disease, may play a physiological role in microbial entrapment and innate immunity. Rehabilitation of a β-amyloid bad boy A protein called Aβ is thought to cause neuronal death in Alzheimer’s disease (AD). Aβ forms insoluble aggregates in the brains of patients with AD, which are a hallmark of the disease. Aβ and its propensity for aggregation are widely viewed as intrinsically abnormal. However, in new work, Kumar et al. show that Aβ is a natural antibiotic that protects the brain from infection. Most surprisingly, Aβ aggregates trap and imprison bacterial pathogens. It remains unclear whether Aβ is fighting a real or falsely perceived infection in AD. However, in any case, these findings identify inflammatory pathways as potential new drug targets for treating AD. The amyloid-β peptide (Aβ) is a key protein in Alzheimer’s disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.

Subfields: Biological Psychiatry, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/d610eddc2ccc4ab9ed474292a41d15a9ae79b7c9

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Citations in the corpus

Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease (2016, positive): “Given the structure of aSyn and its ability to associate with membranes (Jo et al., 2000), it is tempting to speculate that extracellular aSyn may act as an antimicrobial, similar to recent observations with amyloid beta (Kumar et al., 2016), and shape the PD microbiome.”
The blood–brain barrier in health and disease: Important unanswered questions (2020, background): “Leakage is evident within hours of the primary insult, is subsequently reduced, and then reappears the day after (Huang et al., 1999; Kuroiwa et al., 1985; Fig.”
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, neutral): “Aβ also forms fibrils that entrap bacteria and fungal cells, leading to agglutination in vitro (Kumar et al., 2016; Spitzer et al., 2016).”
The Central Nervous System and the Gut Microbiome (2016, background): “Interestingly, a recent report suggests that a physiologic role of the amyloid protein Ab, known to form pathogenic plaques in AD, is as an antimicrobial agent to eliminate bacterial infection in the brain (Kumar et al., 2016).”
Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration (2017, background): “Simultaneously, a growing body of research is investigating the microbial basis for triggering Aβ pathology (Kumar et al. 2016).”