Dataset Information

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

ABSTRACT: The amyloid-? peptide (A?) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting that A? is an antimicrobial peptide. We present in vivo data showing that A? expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that A? 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 A? oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating ?-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 ?-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that ?-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 A?, as has been described for other antimicrobial peptides.

SUBMITTER: Kumar DK

PROVIDER: S-EPMC5505565 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Publications

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

Kumar Deepak Kumar Vijaya DK Choi Se Hoon SH Washicosky Kevin J KJ Eimer William A WA Tucker Stephanie S Ghofrani Jessica J Lefkowitz Aaron A McColl Gawain G Goldstein Lee E LE Tanzi Rudolph E RE Moir Robert D RD

Science translational medicine 20160501 340

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, o ...[more]

PMID: 27225182

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Project description:MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

Dataset Information

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

Publications

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

Similar Datasets

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