Multisensory Fusion Training and 7, 8-Dihydroxyflavone Improve Amyloid-ß-Induced Cognitive Impairment, Anxiety, and Depression-Like Behavior in Mice Through Multiple Mechanisms.

Background: There is growing interest in the role of physical activity in patients with of Alzheimer's disease (AD), particularly regarding its impact of cognitive function, gut microbiota, metabolites, and neurotrophic factors. Objective: To investigate the impact of multisensory fusion training (MSFT) combined with 7, 8-dihydroxyflavone (DHF) on the behavioral characteristics, protein expression, microbiome, and serum metabolome using the AD model in mice induced with amyloid-ß (Aß). Methods: We assessed cognitive ability, anxiety-like and depression-like behaviors in Aß mice using behavioral measures. Western blotting was employed to detect the expression of relevant proteins. The 16S rRNA gene sequencing and metabolomics were used to analyze changes in the intestinal microbial composition and serum metabolic profile, respectively, of Aß mice. Results: The behavioral outcomes indicated that a 4-week intervention combining DHF and MSFT yielded remarkable improvements in cognitive function and reduced anxiety and depression-like behaviors in Aß mice. In the hippocampus of Aß mice, the combined intervention increased the levels of BDNF, VGF, PSD-95, Nrf2, p-GSK3ß and p-CREB proteins. Analyses of sequence and metabolomic data revealed that Bacteroides and Ruminococcaceae were remarkably more abundant following the combined intervention, influencing the expression of specific metabolites directly linked to the maintenance of neuronal and neurobehavioral functions. These metabolites play a crucial role in vital processes, such as amino acid metabolism, lipid metabolism, and neurotransmitter metabolism in mice. Conclusion: Our study highlighted that MSFT combined with DHF improves cognitive impairment, anxiety, and depression-like behavior in Aß mice through multiple mechanisms, and further validated the correlation between the gut microbiome and serum metabolome. These findings open up a promising avenue for future investigations into potential treatment strategies for AD.

Characterization of vB_VpaP_MGD2, a newly isolated bacteriophage with biocontrol potential against multidrug-resistant Vibrio parahaemolyticus.

Vibrio parahaemolyticus is a major foodborne pathogen and is also pathogenic to shrimp. Due to the emergence of multidrug-resistant V. parahaemolyticus strains, bacteriophages have shown promise as antimicrobial agents that could be used for controlling antibiotic-resistant strains. Here, a V. parahaemolyticus phage, vB_VpaP_MGD2, was isolated from a clam (Meretrix meretrix) and further characterized to evaluate its potential capability for biocontrol. Podophage vB_VpaP_MGD2 had a wide host range and was able to lyse 27 antibiotic-resistant V. parahaemolyticus strains. A one-step growth curve showed that vB_VpaP_MGD2 has a short latent period of 10 min and a large burst size of 244 phages per cell. Phage vB_VpaP_MGD2 was able to tolerate a wide range of temperature (30 °C-50 °C) and pH (pH 3-pH 10). Two multidrug-resistant strains (SH06 and SA411) were suppressed by treatment with phage vB_VpaP_MGD2 at a multiplicity of infection of 100 for 24 h without apparent regrowth of bacterial populations. The frequency of mutations causing bacteriophage resistance was relatively low (3.1 × 10-6). Phage vB_VpaP_MGD2 has a double-stranded DNA with a genome size of 45,105 bp. Among the 48 open reading frames annotated in the genome, no lysogenic genes or virulence genes were detected. Sequence comparisons suggested that vB_VpaP_MGD2 is a member of a new species in the genus Zindervirus within the subfamily Autographivirinae. This is the first report of a member of the genus Zindervirus that can infect V. parahaemolyticus. These findings suggest that vB_VpaP_MGD2 may be a candidate biocontrol agent against early mortality syndrome/acute hepatopancreatic necrosis disease (EMS/AHPND) caused by multidrug-resistant V. parahaemolyticus in shrimp production.

Calcium-Sensing Receptor Mediates ß-Amyloid-Induced Synaptic Formation Impairment and Cognitive Deficits via Regulation of Cytosolic Phospholipase A2/Prostaglandin E2 Metabolic Pathway.

Calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCRs). Soluble ß-amyloid peptide (Aß) is one of the orthosteric modulators of CaSR, while, the role and underlying mechanism of CaSR in cognitive decline in Alzheimer's disease (AD) is unclear. In this study, molecular technology such as live-cell imaging combined with behavioral tests were used to explore the role and the underlying mechanism of CaSR in the cognitive deficits in AD mice. The expression levels of CaSR were increased both in AD mice and Aß1-42 (ß-amyloid protein)-treated primary cultured neurons. Pharmacological inhibition of CaSR ameliorated recognitive and spatial memory deficits of Aß1-42-oligomer-treated mice in a dose-dependent manner. Pharmacological inhibition of CaSR or down-regulation of the expression of CaSR by CaSR-shRNA-lentivirus prevented the impairment of filopodia, and the synapse induced by oligomeric Aß1-42. The contents of cytosolic phospholipase A2 (cPLA2) and prostaglandin E2 (PGE2) in hippocampal neurons and tissue were increased after treatment with Aß1-42 oligomers. Inhibition or down-regulation of CaSR mediates Aß-induced synapse formation and cognitive deficits partially, through the activation of the cPLA2/PGE2 pathway. This study provides novel insights on CaSR, which is a promising therapeutic target for AD.

Pharmacological Mechanisms Underlying the Neuroprotective Effects of Alpinia oxyphylla Miq. on Alzheimer's Disease.

Alpinia oxyphylla Miq. (i.e., A. oxyphylla), a traditional Chinese medicine, can exert neuroprotective effects in ameliorating mild cognitive impairment and improving the pathological hallmarks of Alzheimer's disease (AD). Here, 50 active compounds and 164 putative targets were collected and identified with 251 clinically tested AD-associated target proteins using network pharmacology approaches. Based on the Gene Ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichments, the compound-target-pathway-disease/protein-protein interaction network constructions, and the network topological analysis, we concluded that A. oxyphylla may have neuroprotective effects by regulating neurotransmitter function, as well as brain plasticity in neuronal networks. Moreover, closely-related AD proteins, including the amyloid-beta precursor protein, the estrogen receptor 1, acetylcholinesterase, and nitric oxide synthase 2, were selected as the bottleneck nodes of network for further verification by molecular docking. Our analytical results demonstrated that terpene, as the main compound of A. oxyphylla extract, exerts neuroprotective effects, providing new insights into the development of a natural therapy for the prevention and treatment of AD.