Sci Transl Med. 2016 May 25;8(340):340ra72.
Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease.
Kumar DK1, Choi SH1, Washicosky KJ1, Eimer WA1, Tucker S1, Ghofrani J1, Lefkowitz A1, et al.
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.
PMID: 27225182
PubMed Commons:
Claudiu Bandea 2016 May 28 8:06 p.m.
Remarkable results, questionable report
"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" (1). Indeed, fascinating findings. What Kumar et al. did not articulate, though, is that their result is one of many findings, observations, and arguments supporting the theory (2,3) that:
(i) β-amyloid, tau, α-synuclein, huntingtin, TDP-43, prion protein and other primary proteins implicated in neurodegenerative diseases are members of the innate immune system;
(ii) The isomeric conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire;
(iii) The immune reactions and activities associated with the function of these proteins in innate immunity lead to Alzheimer’s, Parkinson’s, Huntington’s, ALS and Creutzfeldt-Jakob Disease, which are innate immunity disorders.
Generating data and observations, although essential, represents only half of the scientific process; the other is their interpretation and integration into the existing knowledge and paradigms. That’s where the article by Kumar et al. falls short.
Perhaps the authors were not fully familiar with the literature and paradigms in the field of neurodegenerative diseases. Or, perhaps, Kumar et al. did not consider it relevant to discuss their results in the context of previous findings, ideas and hypotheses. For example, the authors did not address or explain their results in context of the ‘prion’ paradigm, which has dominated the thinking in the field of Alzheimer’s and other neurodegenerative diseases in the last few years (e.g. 4,5,6,7). Nor did they refer to a related study entitled "Alpha-synuclein expression restricts RNA viral infections in the brain" (8), which is highly relevant considering the fact that alpha-synuclein, a putative member of the innate immune system and the primary protein implicated in Parkinson’s, is a significant player in Alzheimer’s disease. Also, some might consider highly questionable leaving out the study by Kobayashi et al. entitled "Binding sites on tau proteins as components for antimicrobial peptides" (9).
Given these omissions, it's no wonder in her The New York Times article on Kumar et al. study, Gina Kolata wrote: "The Harvard researchers report a scenario seemingly out of science fiction".
Some health myths never die, even if they're based on pseudo science.
