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Intestinal Microbial Dysbiosis Aggravates the Progression of Alzheimer's Disease in Drosophila

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Intestinal Microbial Dysbiosis Aggravates the Progression of Alzheimer's Disease in Drosophila

Shih-Cheng Wu et al. Nat Commun.

Abstract

Neuroinflammation caused by local deposits of Aβ42 in the brain is key for the pathogenesis and progression of Alzheimer's disease. However, inflammation in the brain is not always a response to local primary insults. Gut microbiota dysbiosis, which is recently emerging as a risk factor for psychiatric disorders, can also initiate a brain inflammatory response. It still remains unclear however, whether enteric dysbiosis also contributes to Alzheimer's disease. Here we show that in a Drosophila Alzheimer's disease model, enterobacteria infection exacerbated progression of Alzheimer's disease by promoting immune hemocyte recruitment to the brain, thereby provoking TNF-JNK mediated neurodegeneration. Genetic depletion of hemocytes attenuates neuroinflammation and alleviated neurodegeneration. We further found that enteric infection increases the motility of the hemocytes, making them more readily attracted to the brain with an elevated oxidative stress status. This work highlights the importance of gut-brain crosstalk as a fundamental regulatory system in modulating Alzheimer's disease neurodegeneration.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Enteric dysbiosis aggravates neurodegeneration in a Drosophila Alzheimer’s disease (AD) model. a Histology analysis of degenerated brain tissues (brain section; 14 days postinfection, dpi; n = 10) and immunohistochemistry staining of apoptosis markers (whole brain; 10 dpi; n = 15). b, c Negative geotaxis assay of locomotion behavior (n = 120 in each group) b and lifespan analysis (n = 100 in each group) c. elav >Aβ42 transgenic or control (elav alone) flies intestinally infected with or without Ecc15. Error bars represent the SD. The definition of neurodegeneration index is shown in figure legend of Supplementary Fig. 1. H&E, haematoxylin and eosin. **P < 0.01, ***P < 0.001; NS not significant. Scale bars, 50 μm
Fig. 2
Fig. 2
Enteric dysbiosis remotely triggers inflammatory responses in amyloid transgenic fly brain. ac eiger expression and JNK activity in brains of amyloid transgenic flies with or without Ecc15 infection. eiger mRNA expression analyzed by quantitative RT-PCR (qRT-PCR) a, JNK phosphorylation/activation analyzed by immunostaining b and western blotting c with anti-phospho-JNK antibody. d, e Neurodegeneration d and lifespan e analysis after enteric Ecc15 infection, in Eiger-depleted brain (elav > egr-RNAi). f, g qRT-PCR f and confocal microscopy g analysis of brain AMP levels after Ecc15 enteric infection. Repo staining (red), glial cells; GFP signals (green) of reporter gene expressions in Dpt- and Drs-GFP lines. h, i Brain oxidative stress after enteric infection. Confocal imaging of DCF-DA (green) and Elav (red, neuronal cells) signals h. Quantification of DCF-DA fluorescent signals (upper panel) and western blot analysis of gstD-GFP reporter expressions with anti-GFP antibody (lower panel) in i. elav > Aβ42 transgenic or control (elav alone) flies with or without Ecc15 intestinal infection assayed at 10 dpi for eiger expression, AMP response and ROS stress. Error bars represent the SD of at least three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001; NS, not significant. H&E, haematoxylin and eosin. Dpt, Diptericin. Drs, Drosomycin. AttA, Attacin-A. CecA1, Cecropin A1. gstD, glutathione S-transferase D1. Scale bars, 50 μm b, d and upper h; 10 μm g and lower h
Fig. 3
Fig. 3
Macrophage recruitment to amyloid transgenic fly brain aggravates neurodegeneration upon intestinal infection. a Immunostaining of plasmatocyte (green, NimC1 signals) recruited to the transgenic brain upon intestinal infection; n = 15 in each group for quantification (right panel). yellow, mushroom body (FasII signals); blue, DAPI signal; left panel. b, c Immunostaining of the recruited hemocytes (upper and middle panels) and brain histology (lower panel) b and life span analysis c in the transgenic flies with or without dom 1 /l(3)hem 2 hemocyte-deficient background. Green, NimC1 signals; blue, DAPI signal; n = 10 in each group for quantification of brain histology; n = 100 in each group for lifespan assay. d Coimmunostaining of NimC1 and Eiger in brains of the Ecc15-infected transgenic flies. (Right panel shows high magnification view from white dotted line labeled region of left panel). The location of Mushroom body is masked with yellow dotted lines; Eiger, red; recruited plasmatocytes, green; transgenic brain, blue. eg qRT-PCR analysis of eiger expression e and immunostaining f as well as western blot analysis g of JNK phosphorylation in brains of the transgenic flies with or without hemocyte-deficient background. Quantitative data are presented as the mean±SD of three independent experiments. elav>Aβ42 transgenic or control (elav alone) flies with or without Ecc15 intestinal infection were analyzed at 10 dpi for plasmatocyte recruitment, eiger expression, and JNK activation. *P < 0.05, ***P < 0.001; NS, not significant, H&E, haematoxylin and eosin. Scale bars, 50 μm
Fig. 4
Fig. 4
Gut–brain axis mediates the mobilization of hemocytes and their attraction to the transgenic brain in promoting neurodegeneration. a Time-lapse analysis of plasmatocyte migration after enteric infection. Representative examples of the migration trajectories of plasmatocytes (n = 6 in each group). b, c Coimmunostaining of phospho-FAK and NimC1 in plasmatocytes recruited transgenic brains b or in circulation c. Phospho-FAK, red; plasmatocytes, green (n = 15 in each group). d DCF-DA (upper panel) and NimC1 (middle panel) staining and histology (bottom panel) in the transgenic brains with or without overexpressing Jafrac1. e DCF-DA staining in transgenic brains with or without hemocyte deficient background. elav > Aβ42 transgenic or control (elav alone) flies with or without Ecc15 intestinal infection were analyzed at 10 dpi. DCF-DA signal, ROS stress; NimC1 signal, plasmatocyte. Brain histology, n = 10 each group. Quantitative data are presented as the mean±SD of three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001; NS, not significant, H&E, haematoxylin and eosin. Scale bars, 50 μm b, d and e; 5 μm c

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References

    1. Querfurth HW, LaFerla FM. Alzheimer’s disease. N. Engl. J. Med. 2010;362:329–44. doi: 10.1056/NEJMra0909142. - DOI - PubMed
    1. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148:1204–22. doi: 10.1016/j.cell.2012.02.040. - DOI - PMC - PubMed
    1. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 2011;10:698–712. doi: 10.1038/nrd3505. - DOI - PubMed
    1. Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015;17:565–76. doi: 10.1016/j.chom.2015.04.011. - DOI - PMC - PubMed
    1. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 2012;13:701–12. doi: 10.1038/nrn3346. - DOI - PubMed

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