Abstract
Alzheimer’s disease (AD) is characterized by amyloid-β accumulation in the brain and hyperphosphorylated tau aggregation, as well as neuroinflammation. The gut–brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling. Here we investigate interactions between orally ingested chiral Au nanoparticles and the gut microbiota in AD mice. Oral administration of chiral Au nanoparticles restored cognitive abilities and ameliorated amyloid-β and hyperphosphorylated tau pathologies in AD mice via alterations in the gut microbiome composition and an increase in the gut metabolite, indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls. Oral administration of indole-3-acetic acid was able to penetrate the blood–brain barrier and alleviated cognitive decline and pathology including neuroinflammation in AD mice. These findings provide a promising therapeutic target for the amelioration of neuroinflammation and treatment of neurodegenerative diseases.
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Data availability
Source data are provided with this paper. Any additional data generated and analyzed in this study are available from the corresponding authors upon reasonable request. Raw reads of 16S rRNA-sequencing were uploaded to the National Center for Biotechnology Information Sequence Read Archive database (accession number: PRJNA1014784; http://www.ncbi.nlm.nih.gov/bioproject/1014784) or Figshare (https://figshare.com/articles/online_resource/16S_rRNA_zip/24187827).
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Acknowledgements
H.K., C.X. and L.X. acknowledge support from the National Natural Science Foundation of China, grant nos. 21925402, 92156003 and 32071400, respectively.
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L.X., H.K. and C.X. conceived the project and planned the experiments. X.G. and C.L. fabricated and characterized chiral NPs. X.G. and J.Z. carried out experiments in vivo and in vitro. M.S. assisted with the animal behavioral tests. J.X. provided assistance in collecting clinical samples and information. L.X., H.K. and C.X. conceptualized the work. All authors wrote the manuscript and compiled figures, with discussion of results and feedback on the manuscript.
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Extended data
Extended Data Fig. 1 Pathologies of APP/PS1 AD mice through FMT (n = 6).
(A) Immunofluorescence of Aβ (red) and p-tau (green) in the hippocampus. (B) Representative immunostaining for Aβ (black arrows) and p-tau (black arrows) protein. (C) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 60 days). l-Au→AD: fecal microbiota was transplanted from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, into receptor APP/PS1 AD mice. HT of l-Au→AD: Heat-treatment (HT) of fecal microbiota from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, were transplanted into receptor APP/PS1 AD mice. Scale bars, 50 μm. ‘AD’ stands for APP/PS1 AD model mice. Each ‘n’ represents an independent biological sample.
Extended Data Fig. 2 Restoration of cognition abilities and pathologies of 3xTg AD mice through oral administration of IAA (n = 6).
(A) Immunofluorescence of Aβ (red) and p-tau (green) in the hippocampus. (B) Representative immunostaining for Aβ (black arrows) and p-tau (black arrows) protein. (C) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 45 days). Scale bars, 50 μm. CH-223191, the AHR inhibitor. Each ‘n’ represents an independent biological sample.
Extended Data Fig. 3 Restoration of cognition abilities and pathologies of APP/PS1 AD mice through oral administration of IAA and co-housed with WT or APP/PS1 AD mice (n = 6).
(A) Overview of the experimental design in the effects of microbiota on IAA function. (B) The latent period to find the escape platform in water maze of mice with different treatments for 15 days, 30 days, and 45 days, respectively. (C) Track sheets in water maze of mice with treatments for 45 days. (D) Novel object recognition (NOR) test of mice with different treatments for 45 days. (E) Track sheets in NOR test of mice with treatments for 45 days. (F) Aβ and (G) p-tau concentrations in CSF in 45 days. (H) Immunofluorescence of Aβ (red) and p-tau (green) in the hippocampus. (I) Representative immunostaining for Aβ (black arrows) and p-tau (black arrows) protein. (J) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 45 days). i.g: Intragastric administration. IAA co-housed with AD: APP/PS1 AD mice oral administrated of IAA that were housed with APP/PS1 AD mice without treatment. Scale bars, 50 μm. ‘AD’ stands for APP/PS1 AD model mice. Each ‘n’ represents an independent biological sample. One dot represents one mouse. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. Two-tailed unpaired Student’s t-test (D), one-way (B, F, and G) ANOVA, followed by Tukey’s multiple comparisons test.
Extended Data Fig. 4 Alteration of the ability of tryptophan metabolism to produce IAA in APP/PS1 AD mice after oral administration l-Au NPs (n = 6).
(A) Schematic of the 13C10-IAA produced by 13C11- Trp in APP/PS1 AD mice experimental design. (B-C) Relative abundance of 13C10-IAA in APP/PS1 AD mice serum after oral administration of 13C11- Trp, or 13C11- Trp and l-Au NPs 8 h. i.g: Intragastric administration. Each ‘n’ represents an independent biological sample. One dot represents one mouse. Data are represented as the mean ± SD. ***p < 0.001. Two-tailed unpaired Student’s t-test.
Extended Data Fig. 5 Neuroinflammations in mice oral administration with Au NPs and FMT mice (n = 6).
Contents of (A) IL6, (B) TNF-α, and (C) IL1β in the CSF of APP/PS1 AD mice after oral administration of l-, d-, and t-Au NPs. Contents of (D) IL6, (E) TNF-α, and (F) IL1β in the CSF of FMT mice. l-Au→AD: fecal microbiota were transplanted from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, into receptor APP/PS1 AD mice. HT of l-Au→AD: Heat-treatment (HT) of fecal microbiota from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, were transplanted into receptor APP/PS1 AD mice. ‘AD’ stands for APP/PS1 AD model mice. Each ‘n’ represents an independent biological sample. One dot represents one mouse. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way ANOVA followed by Tukey’s multiple comparisons test.
Extended Data Fig. 6 Activated state of microglia cells line BV2, astrocytes cells line MA-c in vitro after IAA treatment (n = 6).
Detection of activated (A) M1(CD68+CD86+), (B) M2 (CD206+CD163+) microglia cell line BV2 and (C) A1, (D) A2 astrocyte cell line MA-c by flow cytometry. (E) Detection of activated M1, M2 microglia cell line BV2 and A1, A2 astrocyte cell line MA-c by confocal. Scale bars, 20 μm. CH-223191, the AHR inhibitor. Box plots extend from the 25th to the 75th percentile with the median value shown as a black line in the middle, and whiskers denote the minima and maxima values. Each ‘n’ represents an independent biological sample. One dot represents one sample. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way (A-D) ANOVA followed by Tukey’s multiple comparisons test.
Extended Data Fig. 7 The cognition abilities and pathologies of 3xTg AD mice through oral administration of IAA after depleted Treg or microglia cells (n = 6).
(A) Overview of the experimental design to explore the key targets of IAA. (B) The latent period to find the escape platform in water maze of mice with different treatments for 15 days, 30 days, and 45 days, respectively. (C) Track sheets in water maze of mice with treatments for 45 days. (D) Novel object recognition (NOR) test of mice with different treatments for 45 days. (E) Track sheets in NOR test of mice with treatments for 45 days. (F) Aβ and (G) p-tau concentrations in CSF in 45 days. (H) Immunofluorescence of Aβ (red) and p-tau (green) in the hippocampus. (I) Representative immunostaining for Aβ (black arrows) and p-tau (black arrows) protein. (J) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 45 days). Scale bars, 50 μm. PLX, PLX3397. i.g: Intragastric administration. Each ‘n’ represents an independent biological sample. One dot represents one mouse. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. Two-tailed unpaired Student’s t-test (D), one-way (B, F, and G) ANOVA, followed by Tukey’s multiple comparisons test. To explore the role of cells, we transiently depleted Treg or microglia cells in 3xTg AD mice (Extended Data Fig. 7a). After depletion of Treg by anti-CD25, 3xTg AD mice showed the improved cognitive function in both Morris water maze experiment and novel object recognition test after treatment with IAA for approximately 45 days, whereas 3xTg AD depleted microglia cells did not (Extended Data Fig. 7b–e). The contents of Aβ and p-tau in the CSF of 3xTg AD mice depleted Treg cells after treatment with IAA for 45 days were the same as those of the WT mice (Extended Data Fig. 7f,g), which also verified by immunohistochemical and immunofluorescence analyses (Extended Data Fig. 7h,i). Nissl staining of the hippocampus in 3xTg AD mice depleted Treg cells showed that the nuclei of the neurons were intact and that the number of neurons had increased after oral administrated of IAA for 45 days, compared with those of 3xTg AD mice (Extended Data Fig. 7j). To be noticed, the concentrations of Aβ and p-tau in CSF, immunohistochemical and immunofluorescence analysis of 3xTg AD mice depleted microglia cells have no any improvements on oral administration with IAA for 45 days.
Extended Data Fig. 8 Impact of IAA on the systemic immune cell population of the 3xTg AD mice (n = 6).
Percentages of (A)Treg cells in CD4+ T cells, (B)TH17 in CD4+ T cells, and (C) IL17+γδT cells in γδ T cells in the colon of 3xTg AD mice. Percentages of (D)Treg cells in CD4+ T cells, (E)TH17 in CD4+ T cells, and (F) IL17+γδT cells in γδ T cells in the periphery of 3xTg AD mice. Percentages of (G)Treg cells in CD4+ T cells, (H)TH17 in CD4+ T cells, and (I) IL17+γδT cells in γδ T cells in the meninges of 3xTg AD mice. Percentages of (J)Treg cells in CD4+ T cells, (K)TH17 in CD4+ T cells, and (L) IL17+γδT cells in γδ T cells in the brain of 3xTg AD mice. CH-223191, the AHR inhibitor. Each ‘n’ represents an independent biological sample. One dot represents one mouse. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way ANOVA followed by Tukey’s multiple comparisons test. The results displayed the increase in Treg cells and decrease in TH17 and IL17γδT cells in the colon, peripheral and meninges of 3xTg AD mice after treatment with IAA for 45 days. On the contrary, 3xTg AD mice without IAA treatment triggered the decrease in Treg cells and the increase in TH17 and IL17γδT cells in colon, peripheral and meninges. While 3xTg AD mice treated with IAA and CH-223191(an AHR inhibitor), the percentage of Treg cells, TH17 cells, and IL17γδT cells had no changes, which was the same as 3xTg AD mice without IAA treatment. Noticeably, these cells in brain parenchyma were almost no affected.
Extended Data Fig. 9 The inflammasome activity of primary microglia, primary astrocytes cell, microglial cells line BV2, and astrocyte cell line MA-c after treated with IAA in vitro (n = 6).
(A) levels of NLRP3 in microglia cell line BV2 and astrocyte cell line MA-c were determined confocally. Scale bars, 20 μm. (B) Western blot analysis of microglia cell line BV2 and astrocyte cell line MA-c for NLRP3, pro-caspase 1, caspase 1, ASC, pro-IL18, IL18, pro-IL1β, IL1β, NF-κB and β-actin, respectively. The expression levels of NLRP3, caspase-1, IL1β and IL18 in (C) microglial cell line BV2 and (D) astrocyte cell line MA-c were detected by RT-qPCR. Contents of IL18 and IL1β in (E) primary microglia and (F) primary astrocytes cell were determined by ELISA. Contents of IL18 and IL1β in (G) microglia cell line BV2 and (H) astrocyte cell line MA-c were determined by ELISA. CH-223191, the AHR inhibitor. Each ‘n’ represents an independent biological sample. One dot represents one sample. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way (C-H) ANOVA followed by Tukey’s multiple comparisons test.
Extended Data Fig. 10 The way of Au NPs interacts with bacteria.
(A) Zeta potential of PEGylated Au NPs (n = 3). (B) Confocal and (C) SEM images of L.reuteri incubated with l-Au NPs (n = 6). ITC data and integrated heat data with respect to time for the titration of Trp to (D) l-Au NPs (E) d-Au NPs (F) t-Au NPs. The (G) absorbance (H) CD and (I) Fluorescence of remaining Trp in the supernatant after coincubation of Au NPs with Trp. Scale bars, 2 μm. Each ‘n’ represents an independent sample. Data are represented as the mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way (A) followed by Tukey’s multiple comparisons test.
Supplementary information
Supplementary Information
Supplementary materials and methods, Figs. 1–18 and references.
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Supplementary Table 1
KEGG pathway enrichment analysis of feces metabolites in APP/PS1 AD mice with or without oral administration of ʟ-Au NPs.
Supplementary Table 2
RT–qPCR primer sequence.
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Guo, X., Li, C., Zhang, J. et al. Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut–brain axis. Nat Aging 3, 1415–1429 (2023). https://doi.org/10.1038/s43587-023-00516-9
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DOI: https://doi.org/10.1038/s43587-023-00516-9
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