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2 results on '"PS1 mice"'

1. Microglial PD‐1 stimulation by astrocytic PD‐L1 suppresses neuroinflammation and Alzheimer's disease pathology.

Author

Kummer, Markus P, Ising, Christina, Kummer, Christiane, Sarlus, Heela, Griep, Angelika, Vieira‐Saecker, Ana, Schwartz, Stephanie, Halle, Annett, Brückner, Matthias, Händler, Kristian, Schultze, Joachim L, Beyer, Marc, Latz, Eicke, and Heneka, Michael T

Subjects
*MICROGLIA, *PATHOLOGY, *ALZHEIMER'S disease, *PROGRAMMED death-ligand 1, *PROGRAMMED cell death 1 receptors, *NEUROINFLAMMATION, *AMYLOID plaque
Abstract

Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune‐cell checkpoint receptor/ligand pair PD‐1/PD‐L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD‐L1 and PD‐1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD‐L1 from astrocytes, which may mediate ectodomain signaling to PD‐1‐expressing microglia. Deletion of microglial PD‐1 evoked an inflammatory response and compromised amyloid‐β peptide (Aβ) uptake. APP/PS1 mice deficient for PD‐1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD‐1/PD‐L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD. SYNOPSIS: Neuroinflammation, a hallmark of Alzheimer's disease (AD), is involved in beta‐amyloid peptide (Aβ) plaque deposition and clearance. Here, the PD‐1/PD‐L1 axis is found as an important pathway for regulating the immune system in the brain, sustaining microglial Aβ uptake and reducing chronic neuroinflammation. Astrocytic PD‐L1 and microglial PD‐1 are upregulated around Aβ plaques in Alzheimer's disease (AD) and APP/PS1 mice.PD‐L1 is secreted in a soluble form by astrocytes in culture.PD‐1 deficiency compromises Aβ phagocytosis and induces an inflammatory response in vitro.Loss of PD‐1 increases Aβ plaque deposition and reduces microglial Aβ uptake in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Published
2021
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2. Qingxin kaiqiao fang ameliorates memory impairment and inhibits apoptosis in APP/PS1 double transgenic mice through the MAPK pathway

Author

Gao,Shiyu, Lin,Jianwei, Wang,Tianqi, Shen,Yan, Li,Yan, Yang,Wenyu, Zhou,Kailiang, and Hu,Haiyan

Subjects
Male, Memory Disorders, Drug Design, Development and Therapy, Qingxin kaiqiao, Apoptosis, Mice, Transgenic, MAPK, Mice, Inbred C57BL, Disease Models, Animal, Mice, Alzheimer Disease, Animals, Mitogen-Activated Protein Kinases, APP, Maze Learning, Alzheimer’s disease, PS1 mice, Original Research, Drugs, Chinese Herbal
Abstract

Shiyu Gao,1,2 Jianwei Lin,1,2 Tianqi Wang,1,2 Yan Shen,1,2 Yan Li,1,2 Wenyu Yang,1,2 Kailiang Zhou,2–4 Haiyan Hu1,2 1Department of Traditional Chinese Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China; 2The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325003, China; 3Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China; 4Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China Background: Qingxin kaiqiao fang (QKF) has been found to treat Alzheimer’s disease (AD) through apoptosis inhibition. The mitogen-activated protein kinase (MAPK) pathway is closely related to apoptosis in the course of AD. This study aimed to investigate whether QKF-induced apoptosis depression is achieved through MAPK pathway.Materials and methods: C57BL/6 J and APP/PS1 mice were used as control and model groups. APP/PS1 mice were treated with different dosages of QKF (4.75, 9.5, and 19 g·kg-1·d-1·ig, respectively) for 12 weeks as L-QKF, M-QKF, and H-QKF groups. The M-QKF-treated APP/PS1 mice were administrated with 2 µg/kg of U46619 and saline, intra ventricular ventricle injection, as M-QKF+U46619 and M-QKF+saline groups and were injected with PD98059 0.3 mg/kg and the same volume of dimethyl sulfoxide (DMSO), intravenous, as M-QKF+PD98059 and M-QKF+DMSO groups. After 12 weeks treatment, Morris water maze was performed for behavior study. Pathological degeneration was examined by H&E staining, Nissl staining, and transmission electron microscope observation of hippocampus; immunohistochemistry and Western blot (WB) were tested for amyloid β (Aβ) expression. Apoptosis was measured through TUNEL assay; Bax, Bcl-2, and caspase-3 expression through WB; and cleaved caspase-3 expression through ELISA. MAPK pathway was detected via WB for the expressions of ERK1/2, JNK, and p38 MAPK and their phosphorylation patterns.Results: QKF improved the learning and memory capability, as well as inhibited neuronal apoptosis and then reduced the pathological degeneration of APP/PS1 mice. M-QKF reduced neuron apoptosis by inhibiting p38 MAPK and activating ERK1/2 but had no significant effect on JNK.Conclusion: QKF, especially at the middle dose, alleviated the learning and memory impairment and played an antiapoptotic role in AD through MAPK pathways. Keywords: Qingxin kaiqiao, Alzheimer’s disease, apoptosis, APP, PS1 mice, MAPK

Published
2019

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