Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer's disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted 1 week (1 W), 2 months (2 M), and 6 months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ1-42. The results suggested that memory impairment emerged as early as 1 W, peaked at 2 M, and lasted until 6 M after injection. Chronic treatment with rolipram (0.1, 0.5, 1.0 mg/kg/d, i.p.) for 2 weeks (i.e., treatment started at 1.5 months after Aβ1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed the Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor, and glucocorticoid receptors (CRF-R and GR) levels, whereas it decreases in brain-derived neurotropic factor (BDNF) and the ratio of pCREB to CREB expression. These effects of rolipram were prevented by pre-treatment with PKA inhibitor H89. The findings indicated that the protective effects of rolipram against Aβ1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.

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Background As a domesticated species vital to humans, horses are raised worldwide as a source of mechanical energy for sports, leisure, food production, and transportation. The gut microbiota plays an important role in the health, diseases, athletic performance, and behaviour of horses. Results Here, using approximately 2.2 Tb of metagenomic sequencing data from gut samples from 242 horses, including 110 samples from the caecum and 132 samples from the rectum (faeces), we assembled 4142 microbial metagenome-assembled genomes (MAG), 4015 (96.93%) of which appear to correspond to new species. From long-read data, we successfully assembled 13 circular whole-chromosome bacterial genomes representing novel species. The MAG contained over 313,568 predicted carbohydrate-active enzymes (CAZy), over 59.77% of which had low similarity match in CAZy public databases. High abundance and diversity of antibiotic resistance genes (ARG) were identified in the MAG, likely showing the wide use of antibiotics in the management of horse. The abundances of at least 36 MAG (e.g. MAG belonging to Lachnospiraceae, Oscillospiraceae, and Ruminococcus) were higher in racehorses than in nonracehorses. These MAG enriched in racehorses contained every gene in a major pathway for producing acetate and butyrate by fibre fermentation, presenting potential for greater amount of short-chain fatty acids available to fuel athletic performance. Conclusion Overall, we assembled 4142 MAG from short- and long-read sequence data in the horse gut. Our dataset represents an exhaustive microbial genome catalogue for the horse gut microbiome and provides a valuable resource for discovery of performance-enhancing microbes and studies of horse gut microbiome.

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