Astrocytic Lrp4 (Low-density lipoprotein receptor–related protein 4) contributes to ischemia-induced brain injury by regulating ATP release and adenosine-A2AR (Adenosine A2A Receptor) signaling

Xin Chun Ye, Jin Xia Hu, Lei Li, Qiang Li, Fulei Tang, Sen Lin, Dong Sun, Xiang Dong Sun, Gui Yun Cui, Lin Mei, Wencheng Xiong

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.

Original languageEnglish (US)
Pages (from-to)165-174
Number of pages10
JournalStroke
Volume49
Issue number1
DOIs
StatePublished - Jan 1 2018

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Adenosine A2A Receptors
LDL Lipoproteins
Brain Injuries
Astrocytes
Ischemia
Adenosine Triphosphate
Proteins
Stroke
Knockout Mice
Adenosine
Glutamic Acid
Brain
Purinergic P2X Receptors
Adenosine A2 Receptor Antagonists
Oxygen
Glucose
Protein Deficiency
Middle Cerebral Artery Infarction
Synaptic Transmission
Serine

Keywords

  • A2A
  • Adenosine
  • Adenosine
  • Astrocytes
  • Brain injury
  • Ischemia
  • Receptor

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Astrocytic Lrp4 (Low-density lipoprotein receptor–related protein 4) contributes to ischemia-induced brain injury by regulating ATP release and adenosine-A2AR (Adenosine A2A Receptor) signaling. / Ye, Xin Chun; Hu, Jin Xia; Li, Lei; Li, Qiang; Tang, Fulei; Lin, Sen; Sun, Dong; Sun, Xiang Dong; Cui, Gui Yun; Mei, Lin; Xiong, Wencheng.

In: Stroke, Vol. 49, No. 1, 01.01.2018, p. 165-174.

Research output: Contribution to journalArticle

Ye, Xin Chun ; Hu, Jin Xia ; Li, Lei ; Li, Qiang ; Tang, Fulei ; Lin, Sen ; Sun, Dong ; Sun, Xiang Dong ; Cui, Gui Yun ; Mei, Lin ; Xiong, Wencheng. / Astrocytic Lrp4 (Low-density lipoprotein receptor–related protein 4) contributes to ischemia-induced brain injury by regulating ATP release and adenosine-A2AR (Adenosine A2A Receptor) signaling. In: Stroke. 2018 ; Vol. 49, No. 1. pp. 165-174.
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abstract = "Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.",
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author = "Ye, {Xin Chun} and Hu, {Jin Xia} and Lei Li and Qiang Li and Fulei Tang and Sen Lin and Dong Sun and Sun, {Xiang Dong} and Cui, {Gui Yun} and Lin Mei and Wencheng Xiong",
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AU - Ye, Xin Chun

AU - Hu, Jin Xia

AU - Li, Lei

AU - Li, Qiang

AU - Tang, Fulei

AU - Lin, Sen

AU - Sun, Dong

AU - Sun, Xiang Dong

AU - Cui, Gui Yun

AU - Mei, Lin

AU - Xiong, Wencheng

PY - 2018/1/1

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N2 - Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.

AB - Background and Purpose—Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. Methods—The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. Results—Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. Conclusions—The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.

KW - A2A

KW - Adenosine

KW - Adenosine

KW - Astrocytes

KW - Brain injury

KW - Ischemia

KW - Receptor

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