Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease

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...

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Vydané v:	Science translational medicine Ročník 8; číslo 340; s. 340ra72
Hlavní autori:	Kumar, Deepak Kumar Vijaya, Choi, Se Hoon, Washicosky, Kevin J, Eimer, William A, Tucker, Stephanie, Ghofrani, Jessica, Lefkowitz, Aaron, McColl, Gawain, Goldstein, Lee E, Tanzi, Rudolph E, Moir, Robert D
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 25.05.2016
Predmet:	Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - microbiology Amyloid beta-Peptides - genetics Amyloid beta-Peptides - physiology Animals Animals, Genetically Modified Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans - microbiology Disease Models, Animal Female Humans Immunity, Innate - genetics Immunity, Innate - physiology Mice Mice, Transgenic Salmonella typhimurium - pathogenicity
ISSN:	1946-6242, 1946-6242
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1946-6242 1946-6242
DOI:	10.1126/scitranslmed.aaf1059