Increasing evidence indicated that probiotics can be effective in improving behaviors similar to depression and anxiety disorders. However, the underlying mechanisms remain unclear, as is the effects of single vs. combined probiotics on depression and anxiety. This study aimed to determine whether combined probiotics could attenuate depressive-like and anxiety-like behavior induced by chronic unpredictable mild stress (CUMS) and its potential mechanisms. Rats underwent CUMS treatment and then administered Lactobacillus rhamnosus HN001 (HN001) or Bifidobacterium animalis subsp. lactis HN019 (HN019), alone or in combination. Levels of neurotransmitters, inflammatory factors, and the gut microbiota were measured. HN001 and (or) HN019 treatment improved depressive-like and anxiety-like behavior in rats, including increased moving distance and exploratory behavior (p < 0.05). In addition, altered gut microbiota structure induced by CUMS was amended by HN001 and/or HN019 (p < 0.05). HN001 and/or HN019 intervention also remarkably normalized levels of 5-HT, DA, NE, HVA, DOPAC, HIAA, TNF-α, IL-6, IL-18 and IL-1β in CUMS rats (p < 0.05). Furthermore, the effects of combined probiotics on decreasing inflammation and improved gut microbiota (Chao1 index and ACE index, p < 0.05) were superior to the single probiotics. Moreover, spearman analysis showed a certain correlation between the different microbiota, such as Firmicutes, Bacteroidetes, Verrucomicrobias, Proteobacterias and Actinobacterias, and inflammation and neurotransmitters. These findings suggested that CUMS induced depressive and anxiety-like behaviors can be alleviated by the combination of probiotics, which was possibly associated with the alterations in the gut microbiota composition and increased neurotransmitters and decreased inflammatory factors.

Dysbiosis of the gut microbiota is associated with the development of depression, but the underlying mechanism remains unclear. The aim of this study was to determine the relationship between microbiota and NLRP3 inflammasome induced by chronic unpredictable mild stress (CUMS). Fecal transplantation (FMT) experiment was conducted to elucidate the potential mechanism. Levels of NLRP3 inflammasome, microbiota, inflammatory factors and tight junction proteins were measured. CUMS stimulation significantly increased the levels of NLRP3, Caspase-1 and ASC in brain and colon(p<0.05), decreased the levels of tight junction proteins Occludin and ZO-1 (p<0.05). Interestingly, increased NLRP3 inflammasome and inflammatory cytokines and decreased tight junction proteins were found in antibiotic-treated (Abx) rats received CUMS rat fecal microbiota transplantation. Furthermore, fecal microbiota transplantation altered the microbiota in Abx rats, which partially overlapped with that of the donor rats. Importantly, probiotic administration amended the alteration of microbiota induced by CUMS treatment, then reduced the levels of NLRP3 inflammasome and inflammatory factors. In conclusion, these findings suggested that depression-like behaviors induced by CUMS stimulation were related to altered gut microbiota, broke the intestinal barrier, promoted the expression of NLRP3 inflammasome and elevated inflammation. Therefore, improving the composition of microbiota via probiotic can attenuate inflammation by amending the microbiota and suppressing the activation of NLRP3 inflammasome, which is considered as a novel therapeutic strategy for depression.

Alzheimer’s disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component—presenilin 1 (PS1)—in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression.

This article has been retracted, and the online PDF has been watermarked “RETRACTED”. A retraction notice is available at DOI: 10.3233/JAD-239002.

High incidence rate of Alzheimer’s disease (AD) is observed in patients with type 2 diabetes. Aggregated β-amyloid (Aβ) and hyperphosphorylated tau are the hallmarks of AD. Hyperphosphorylated tau has been detected in diabetic animals as well as in diabetic patients. Folates mediate the transfer of one carbon unit, required in various biochemical reactions. The effect of folate on tau phosphorylation in diabetic models still remains unknown. In this study, we investigated the effect and mechanism of folic acid on hyperphosphorylation of tau in streptozotocin (STZ)-induced diabetic mice. Diabetic mice induced by STZ, at the age of 10 weeks, were administered with three levels of folic acid: folic acid-deficient diet, diet with normal folic acid content, and 120 μg/kg folic acid diet for 8 weeks. Levels of serum folate and blood glucose were monitored. Tau phosphorylation, protein phosphatase 2A (PP2A) methylation, and Glycogen synthase kinase 3β (GSK-3β) phosphorylation were detected using Western blot. The S-adenosyl methionine:S-adenosyl homocysteine ratio (SAM:SAH) in brain tissues was also determined. DNA methyltransferase (DNMT) mRNA expression levels were detected using real-time PCR. Folic acid reduced tau hyperphosphorylation at Ser396 in the brain of diabetes mellitus (DM) mice. In addition, PP2A methylation and DNMT1 mRNA expression were significantly increased in DM mice post folic acid treatment. GSK-3β phosphorylation was not regulated by folic acid administration. Folic acid can reduce tau phosphorylation by regulating PP2A methylation in diabetic mice. These results support that folic acid can serve as a multitarget neuronal therapeutic agent for treating diabetes-associated cognitive dysfunction.