title: LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAβPPswe/PS1ΔE9transgenic mice.
abstract: Accumulating evidence implicates the neuroendocrine immunomodulation (NIM) network in the physiopathological mechanism of Alzheimer's disease (AD). Notably, we previously revealed that the NIM network is dysregulated in the PrP-hAβPPswe/PS1ΔE9(APP/PS1) transgenic mouse model of AD.
  
  
  
  After treatment with a novel Liuwei Dihuang formula (LW-AFC), mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-β (Aβ) deposition, and Aβ level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an enzyme-linked immunosorbent assay (ELISA) were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. Data between two groups were compared using a Student's t test. Comparison of the data from multiple groups against one group was performed using a one-way analysis of variance (ANOVA) followed by a Dunnett's post hoc test or a two-way repeated-measures analysis of variance with a Tukey multiple comparisons test.
  
  
  
  LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Aβ deposition in the brain, and reduced the concentration of Aβ1-42in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+T cells, and reduced CD4+CD25+Foxp3+T cells in the spleen lymphocytes, downregulated interleukin (IL)-1β, IL-2, IL-6, IL-23, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-α and -β, and upregulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice.
  
  
  
  LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic mice via the restoration of the NIM network to a greater extent than either memantine or donepezil, which supports the use of LW-AFC as a potential agent for AD therapy.
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.|Guangxi Medical University, Nanning, 530021, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Lei
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. cxr916@163.com.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China. cxr916@163.com.
authors.forename: Xiao-Rui
authors.initials: XR
authors.lastname: Cheng
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.
authors.forename: Xiao-Rui
authors.initials: XR
authors.lastname: Zhang
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Cheng
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.
authors.forename: Yi-Ran
authors.initials: YR
authors.lastname: Xu
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. zhouwx@bmi.ac.cn.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China. zhouwx@bmi.ac.cn.
authors.forename: Wen-Xia
authors.initials: WX
authors.lastname: Zhou
authors.affiliation: Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. zhangyx@bmi.ac.cn.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, 100850, China. zhangyx@bmi.ac.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D016207:Cytokines / Q000187:drug effects*; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D007028:Hypothalamic Hormones / Q000378:metabolism*; D007858:Learning / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016207:Cytokines; D004365:Drugs, Chinese Herbal; D007028:Hypothalamic Hormones; C042579:Liuwei Dihuang Decoction
keywords: Alzheimer’s disease; Amyloid-β; Cytokine; LW-AFC; Lymphocyte subset; Neuroendocrine; Neuron loss; PrP-hAβPPswe/PS1ΔE9 transgenic mouse; cognitive behavior