7 research outputs found
Recommended from our members
Early modulation of the gut microbiome by female sex hormones alters amyloid pathology and microglial function
It is well-established that women are disproportionately affected by Alzheimer’s disease. The mechanisms underlying this sex-specific disparity are not fully understood, but several factors that are often associated-including interactions of sex hormones, genetic factors, and the gut microbiome-likely contribute to the disease's etiology. Here, we have examined the role of sex hormones and the gut microbiome in mediating Aβ amyloidosis and neuroinflammation in APPPS1-21 mice. We report that postnatal gut microbiome perturbation in female APPPS1-21 mice leads to an elevation in levels of circulating estradiol. Early stage ovariectomy (OVX) leads to a reduction of plasma estradiol that is correlated with a significant alteration of gut microbiome composition and reduction in Aβ pathology. On the other hand, supplementation of OVX-treated animals with estradiol restores Aβ burden and influences gut microbiome composition. The reduction of Aβ pathology with OVX is paralleled by diminished levels of plaque-associated microglia that acquire a neurodegenerative phenotype (MGnD-type) while estradiol supplementation of OVX-treated animals leads to a restoration of activated microglia around plaques. In summary, our investigation elucidates the complex interplay between sex-specific hormonal modulations, gut microbiome dynamics, metabolic perturbations, and microglial functionality in the pathogenesis of Alzheimer's disease
Evaluating the Robustness of Parameter Estimates in Cognitive Models: A Meta-Analytic Review of Multinomial Processing Tree Models Across the Multiverse of Estimation Methods
Researchers have become increasingly aware that data-analysis decisions affect results. Here, we examine this issue systematically for multinomial processing tree (MPT) models, a popular class of cognitive models for categorical data. Specifically, we examine the robustness of MPT model parameter estimates that arise from two important decisions: the level of data aggregation (complete pooling, no pooling, or partial pooling) and the statistical framework (frequentist or Bayesian). These decisions span a multiverse of estimation methods. We synthesized the data from 13,956 participants (164 published data sets) with a meta-analytic strategy and analyzed the magnitude of divergence between estimation methods for the parameters of nine popular multinomial processing tree (MPT) models in psychology (e.g., process dissociation, source monitoring). We further examined moderators as potential sources of divergence. We found that the absolute divergence between estimation methods was small on average (< .04; with MPT parameters ranging between 0 and 1); in some cases, however, divergence amounted to nearly the maximum possible range (.97). Divergence was partly explained by few moderators (e.g., the specific MPT model parameter, uncertainty in parameter estimation), but not by other plausible candidate moderators (e.g., parameter trade-offs, parameter correlations) or their interactions. Partial-pooling methods showed the smallest divergence within and across levels of pooling and thus seem to be an appropriate default method. Using MPT models as an example, we show how transparency and robustness can be increased in the field of cognitive modeling
Recommended from our members
Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner.
It has recently become well-established that there is a connection between Alzheimers disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each others experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimers disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels
Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia.
We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia. Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aβ deposition
Recommended from our members
Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner
It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis. Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other’s experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice. Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses. Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer’s disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.</p
Additional file 1 of Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner
Additional file 1: Supplemental Figure 1. Gut microbiome composition differs significantly between University of Chicago and Washington University in St. Louis. Analysis of bacterial α-diversity and β-diversity in fecal content from 9-week-old APPPS1-21 male mice collected at the University of Chicago and Washington University in St. Louis. (a) Shannon index, (b) Pielou species evenness. (d) PCoA plot generated by using unweighted unifrac distance metric. Diversity analyses, including alpha and beta diversity, alpha rarefaction, and group significance were analyzed by QIIME and QIIME2. Data are presented as mean SEM. Significance was determined using Two-way ANOVA . *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Supplemental Figure 2. GV-971 targets Aβ plaque halo in a sex-dependent manner. (a) Representative immunofluorescent images of HJ3.4+ Aβ (red) surrounding X34+ Aβ (blue). White * indicates regions of reduced plaque halo. (b,c) Quantification of an average number of HJ3.4 + Aβ surfaces within 5μM X34+ Aβ surface plaque in cortices of 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female = 9-12). Data are presented as mean SEM. Significance was determined using unpaired t-test (d). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Supplemental Figure 3. GV-971 alters amino acid metabolism. GC-nCI-MS and PFBBR derivtization heatmap analysis of metabolite abundance in cecal content from 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female 9-12). Supplemental Figure 4. GV-971 modifies tryptophan metabolism. LCMS/MS heatmap analysis of tryptophan pathway, indole pathway, and kynurenine pathway metabolite concentrations in cecal content from 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female 9-12). Supplemental Figure 5. GV-971 influences primary and secondary bile acid metabolism. LCMS/MS heatmap analysis of primary and secondary bile acid concentrations in cecal content from 5XFAD mice treated with 100mg/kg GV-971 or vehicle (male = 13, female 9-12). Supplemental Figure 6. GV-971 Significantly change peripheral and neuro-cytokine and chemokine production. Pie chart denoting the distribution of cytokine/chemokine production following GV-971 treatment. Chart is characterized into four groups based on expression levels compared to the control groups: Increased, Decreased, Not significant, and Non Detected. (a). Serum analyzed from the University of Chicago APPPS1-21 male and female mice treated with 160mg/kg GV-971. (b). Serum analyzed from Washington University 5XFAD male and female mice treated with 100mg/kg GV-971. (c). Cortical tissue analyzed from Washington University 5XFAD male mice treated with 100mg/kg GV-97. Supplemental Figure 7. GV-971 significantly alters microglia activation and neurodevelopment gene expression. (a). Quantitative PCR analysis of inflammatory, microglial, and neurodevelopment gene expression from bulk cortical tissue of male APPPS1-21 mice treated with GV-971 or vehicle. (b) Quantitative PCR analysis of inflammatory, microglial, and neurodevelopment gene expression from bulk cortical tissue of female APPPS1-21 mice treated with GV-971 or vehicle. Data are presented as mean SEM. Significance was determined using 2 way ANOVA followed by post hoc Tukey’s multiple comparisons. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Supplemental Figure 8. GV-971 alters inflammatory markers in 9 month old 5XFAD male mice. Heat map analysis of bulk RNA in cortices of 5XFAD mice following 100mg/kg GV-971 or vehicle treatment (A) male mice n=13, (B) female mice n= 9-12. Graph generated by hierarchical gene clustering based on groups. Statistical analyses were performed using an unpaired t- test. *, P < 0.05