Intimate metabolic host–microbiome crosstalk regulates immune, metabolic, and neuronal response in health and disease, yet remains untapped for biomarkers or intervention for disease. Our recent study identified an altered microbiome in patients with pre-onset amnestic mild cognitive impairment (aMCI) and dementia Alzheimer’s disease (AD). Thus, we aimed to characterize the gut microbial metabolites among AD, aMCI, and healthy controls (HC). Here, a cohort of 77 individuals (22 aMCI, 27 AD, and 28 HC) was recruited. With the use of liquid-chromatography/gas chromatography mass spectrometry metabolomics profiling, we identified significant differences between AD and HC for tryptophan metabolites, short-chain fatty acids (SCFAs), and lithocholic acid, the majority of which correlated with altered microbiota and cognitive impairment. Notably, tryptophan disorders presented in aMCI and SCFAs decreased progressively from aMCI to AD. Importantly, indole-3-pyruvic acid, a metabolite from tryptophan, was identified as a signature for discrimination and prediction of AD, and five SCFAs for pre-onset and progression of AD. This study showed fecal-based gut microbial signatures were associated with the presence and progression of AD, providing a potential target for microbiota or dietary intervention in AD prevention and support for the host–microbe crosstalk signals in AD pathophysiology.

Background: Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R) injury. The P2X7 receptor (P2X7R) has been reported to be involved in the inflammatory response of many central nervous system diseases. However, the role of P2X7Rs in transient global cerebral I/R injury remains unclear. The purpose of this study is to determine the effects of inhibiting the P2X7R in a rat model of transient global cerebral I/R injury, and then to explore the association between the P2X7R and neuroinflammation after transient global cerebral I/R injury.Methods: Immediately after infusion with the P2X7R antagonists Brilliant blue G (BBG), adenosine 5′-triphosphate-2′,3′-dialdehyde (OxATP) or A-438079, 20 minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. Survival rate was calculated, neuronal death in the hippocampal CA1 region was observed using H & E staining, and DNA cleavage was observed by deoxynucleotidyl transferase-mediated UTP nick end labeling TUNEL). In addition, behavioral deficits were measured using the Morris water maze, and RT-PCR and immunohistochemical staining were performed to measure the expression of IL-1β, TNF-α and IL-6, and to identify activated microglia and astrocytes.Results: The P2X7R antagonists protected against transient global cerebral I/R injury in a dosage-dependent manner. A high dosage of BBG (10 μg) and A-0438079 (3 μg), and a low dosage of OxATP (1 μg) significantly increased survival rates, reduced I/R-induced learning memory deficit, and reduced I/R-induced neuronal death, DNA cleavage, and glial activation and inflammatory cytokine overexpression in the hippocampus.Conclusions: Our study indicates that inhibiting P2X7Rs protects against transient global cerebral I/R injury by reducing the I/R-induced inflammatory response, which suggests inhibition of P2X7Rs may be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury.

Aims: To explore the potential relationships among gut microbiota (GM), local brain spontaneous activity, and neuropsychological characteristics in amnestic mild cognitive impairment (aMCI) patients.Methods: Twenty aMCI and 22 healthy control (HC) subjects were recruited. The GM composition was determined by 16S ribosomal RNA gene sequencing. Resting‐state functional magnetic resonance imaging scans were performed, and fractional amplitude of low‐frequency fluctuations (fALFF) was calculated across different frequencies. The Spearman or Pearson correlation analysis was used to analyze the relationship between spontaneous brain activity and cognitive function, and GM composition.Results: aMCI patients had altered GM state and local spontaneous brain activity as compared with HC subjects. Correlation analysis showed that aMCI and HC groups had different “GM‐intrinsic brain activity interaction” patterns. In aMCI group, at the typical band (0.01‐0.08 Hz), the relative abundance (RA) of Bacteroides from phylum to genus level was negatively correlated with fALFF value of cerebellar vermis IV‐V, and the Ruminococcaceae RA was negatively correlated with fALFF values of left lenticular nucleus and pallidum. The Clostridiaceae RA and Blautia RA were positively correlated with the left cerebellum lobules IV‐V at the slow‐4 band (0.027‐0.073 Hz). The Veillonellaceae RA was positively correlated with fALFF values of left precentral gyrus at the slow‐5 band (0.073‐0.08 Hz). Correlation analysis showed that Clostridium members (Lachnospiraceae and Blautia) were positively, while Veillonellaceae was negatively, correlated with cognition test. Bacteroides was positively correlated with attention and computation, and negatively correlated with the three‐stage command score.Conclusions: aMCI patients have a specific GM‐intrinsic brain activity‐cognitive function interaction pattern.

Although amyloid-β (Aβ) peptide accumulation is considered as a key early event in the pathogenesis of Alzheimer’s disease (AD), the precise pathophysiology of this deadly illness remains unclear and no effective remedies capable of inhibiting disease progression have been discovered. In addition to deposition of extracellular Aβ plaques and intracellular neurofibrillary tangles, neuroinflammation has been identified as the third core characteristic crucial in the pathogenesis of AD. More and more evidence from laboratory and clinical studies have suggested that anti-inflammatory treatments could defer or prevent the occurrence of AD. In this review, we will discuss multifaceted evidence of neuroinflammation presented in AD and the newly emerged anti-inflammatory targets both in pre-clinical and clinical AD.

Alzheimer's disease (AD) is a leading cause of dementia. However, the mechanisms responsible for development of AD, especially for the sporadic variant, are still not clear. In our previous study, we discovered that a small noncoding RNA (miR‐188‐3p) targeting β‐site amyloid precursor protein cleaving enzyme (BACE)‐l, a key enzyme responsible for Aβ formation, plays an important role in the development of neuropathology in AD. In the present study, we identified that miR‐338‐5p, a new miRNA that also targets BACE1, contributes to AD neuropathology. We observed that expression of miR‐338‐5p was significantly down‐regulated in the hippocampus of patients with AD and 5XFAD transgenic (TG) mice, an animal model of AD. Overexpression of miR‐338‐5p in the hippocampus of TG mice reduced BACE1 expression, Aβ formation, and neuroinflammation. Overexpression of miR‐338‐5p functionally prevented impairments in long‐term synaptic plasticity, learning ability, and memory retention in TG mice. In addition, we provide evidence that down‐regulated expression of miR‐338‐5p in AD is regulated through the NF‐κB signaling pathway. Our results suggest that down‐regulated expression of miR‐338‐5p plays an important role in the development of AD.—Qian, Q., Zhang, J., He, F.‐P., Bao, W.‐X., Zheng, T.‐T., Zhou, D.‐M., Pan, H.‐Y., Zhang, H., Zhang, X.‐Q., He, X., Sun, B.‐G., Luo, B.‐Y., Chen, C., Peng, G.‐P. Down‐regulated expression of microRNA‐338‐5p contributes to neuropathology in Alzheimer's disease. FASEB J. 33,4404–4417 (2019). www.fasebj.org

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.