Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering β-Amyloid Accumulation via the Transforming Growth Factor-β (TGFβ)/Smad Signaling Pathway.

Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Aβ1-42 and TGFβ/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFβ/Smad activation and Aβ1-42 expression were reversed by IL17A receptor small interfering RNA and a TGFβ receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

Background/Aims: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. Methods: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer’s disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection. The behavioral changes were evaluated with an open-field test and Morris water maze test on postoperative days 3, 7, and 14. Hippocampal TREM2, DAP12, and interleukin (IL)-1β were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3β (GSK-3β) were also examined in the hippocampus. Results: Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1β expression in the transgenic mice on postoperative days 3 and 7. A corresponding decline in the levels of TREM2 was also found on postoperative days 3, 7, and 14. Overexpression of TREM2 downregulated the levels of IL-1β, ameliorated T396 expression, inhibited the activity of GSK-3β, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression. Conclusion: The downregulation of TREM2 exacerbated surgery-induced cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Overexpression of TREM2 potentially attenuated these effects by decreasing the associated production of proinflammatory cytokines, inhibiting tau hyperphosphorylation, and enhancing synaptophysin expression

Comparative analysis of the hypothalamus transcriptome of laying ducks with different residual feeding intake

ABSTRACT: Feed costs account for approximately 60 to 70% of the cost of poultry farming, and feed utilization is closely related to the profitability of the poultry industry. To understand the causes of the differences in feeding in Shan Partridge ducks, we compared the hypothalamus transcriptome profiles of 2 groups of ducks using RNA-seq. The 2 groups were: 1) low-residual feed intake (LRFI) group with low feed intake but high feed efficiency, and 2) high-residual feed intake (HRFI) group with high feed intake but low feed efficiency. We found 78 DEGs were enriched in 9 differential Kyoto Encyclopedia of Genes and Genome (KEGG) pathways, including neuroactive ligand-receptor interaction, GABAergic synapse, nitrogen metabolism, cAMP signaling pathway, calcium signaling pathway, nitrogen metabolism, tyrosine metabolism, ovarian steroidogenesis, and gluconeogenesis. To further identify core genes among the 78 DEGs, we performed protein-protein interaction and coexpression network analyses. After comprehensive analysis and experimental validation, 4 core genes, namely, glucagon (GCG), cholecystokinin (CCK), gamma-aminobutyric acid type A receptor subunit delta (GABRD), and gamma-aminobutyric acid type A receptor subunit beta1 (GABRB1), were identified as potential core genes responsible for the difference in residual feeding intake between the 2 breeds. We also investigated the level of cholecystokinin (CCK), neuropeptide Y (NPY), peptide YY (PYY), ghrelin, and glucagon-like peptide1 (GLP-1) hormones in the sera of Shan Partridge ducks at different feeding levels and found that there was a difference between the 2 groups with respect to GLP-1 and NPY levels. The findings will serve as a reference for future research on the feeding efficiency of Shan Partridge ducks and assist in promoting their genetic breeding

Surgery-induced cognitive impairment is prevented by concurrent administration of IL17A monoclonal antibody.

<p>Cognitive function was evaluated by Morris water maze (MWM) for 7 days after surgery and by a probe test on postoperative day 3 among mice treated with IL17A monoclonal antibody (SI) or IgG2a control (SC), surgery mice (SA) and control mice (C). (A) Swimming distance; (B) Swimming latency; (C) Time spent in the quadrant with the previously located hidden platform. (D) Spatial working memory was exmined by T maze. Data are represented as means ± SEM. *<i>P</i><0.05; **<i>P</i><0.01 vs. SC3 group and #<i>P</i><0.05; ##<i>P</i><0.01 vs. SA3 group (n = 8).</p

Glial fibrillary acidic protein (GFAP) expression in the hippocampus following hepatectomy in mice.

<p>Representative bands of the hippocampus illustrating expression of GFAP from control group at 1 day (C1), 3 days (C3), and 7 days (C7); from anesthesia group at 1 day (A1), 3 days (A3), and 7 days (A7); or from surgery plus anesthesia group at 1 day (SA1), 3 days (SA3), and 7 days (SA7). Data are represented as the mean ± SEM. *<i>P</i><0.05; **<i>P</i><0.01 vs. C group at the corresponding time point. #<i>P</i><0.05; ##<i>P</i><0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 8).</p

Blockade of IL17A inhibits TGFβ, phospho-Smad2/3 (pSmad2/3), APP, and Aβ_1–42 production in mouse primary astrocyte cultures.

<p>Primary astrocytes were treated with IL17A (25 ng/ml, named IL17 group), rabbit anti-mouse IGg2a (25 ng/ml, named IgG group), or IL17A plus IL17R siRNA (100nM, named IL17Rsi group) for 1, 24, or 48 h. The protein was assessed with Western blotting specific for TGFβ (A), pSmad2/3 (B), APP (C) and Aβ_1–42 (D). Data are represented as means ± SEM. *<i>P</i><0.05; **<i>P</i><0.01 vs. IgG2a group at the corresponding time point. #<i>P</i><0.05; ##<i>P</i><0.01 vs. IL17 Rsi group at the corresponding time point.</p

Performance in the hidden-platform Water Maze Test by hepatectomy surgery mice.

<p>The Morris water maze (MWM) was used to train mice for 5 days before surgery and to test memory formation changes for 7 days after surgery. (A) Latency to find the platform across testing days. (B) Latency to find the platform after surgery. (C) Swim speed across testing days. (D) Swim speed after surgery. (E) Distance to platform across testing days. (F) Distance to platform after surgery. (G) The probe test in the Morris water maze. Data are represented as means ± SEM. *<i>P</i><0.05; **<i>P</i><0.01 vs. C group at the corresponding time point. #<i>P</i><0.05; ##<i>P</i><0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 16).</p

Expression of APP, Aβ_1–42 protein, and phospho-Smad protein in the hippocampus following hepatectomy in mice.

<p>The mRNA and protein measurements of APP <b>(</b>A) and Aβ_1–42 (B) protein in hippocampus were made at 1 day (C1), 3 days (C3), and 7 days (C7) from control group; at 1 day (A1), 3 days (A3), and 7 days (A7) from anesthesia group or at 1 day (SA1), 3 days (SA3), and 7 days (SA7) from surgery plus anesthesia group. (C) phospho-Smad protein (pSmad) was detected by western blotting assay on postoperative day 3. Data are represented as means ± SEM. *<i>P</i><0.05; **<i>P</i><0.01 vs. C group at the corresponding time point. #<i>P</i><0.05; ##<i>P</i><0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 8).</p

Specific primer sequence for real-time PCR.

<p>Specific primer sequence for real-time PCR.</p