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Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L - Nat. Neurosci. (2015)

Bottom Line: Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory.However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known.Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

View Article: PubMed Central - PubMed

Affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.

ABSTRACT
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

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Astrocytic A2A receptor levels are increased in transgenic mice expressing mutant forms of hAPP alone or in combination with a mutant form of PS1(a–d) Representative photomicrographs of hippocampal sections immunostained for the A2A receptor (green) and the astrocyte marker GFAP (red) from nontransgenic (NTG) mice and from transgenic mice expressing hAPP alone (a) or in combination with a mutant form of PS1 (b), transgenic mice expressing a mutant form of human tau (Tau-P301S) (c), or knock-in mice expressing human apoE3 (APOE3-KI) or apoE4 (ApoE4-KI) (d). Ages of the mice are indicated in months (m, left). Cell nuclei were labeled with DAPI (blue). Insets (i–xi) show magnified views of the boxed regions. DGgl: dentate gyrus granular layer. n = 7 NTG and 8 hAPP mice (a); 3 NTG and 5 hAPP/PS1 mice (b); 1 NTG/7 m, 4 Tau-P301S/3 m and 4 Tau-P301S/6.5 m mice (c); 3 APOE3-KI/6 m, 3 APOE3-KI/19 m, 3 APOE4-KI/6 m, and 3 APOE4-KI/17 m mice (d). Scale bars: 50 μm.
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Figure 7: Astrocytic A2A receptor levels are increased in transgenic mice expressing mutant forms of hAPP alone or in combination with a mutant form of PS1(a–d) Representative photomicrographs of hippocampal sections immunostained for the A2A receptor (green) and the astrocyte marker GFAP (red) from nontransgenic (NTG) mice and from transgenic mice expressing hAPP alone (a) or in combination with a mutant form of PS1 (b), transgenic mice expressing a mutant form of human tau (Tau-P301S) (c), or knock-in mice expressing human apoE3 (APOE3-KI) or apoE4 (ApoE4-KI) (d). Ages of the mice are indicated in months (m, left). Cell nuclei were labeled with DAPI (blue). Insets (i–xi) show magnified views of the boxed regions. DGgl: dentate gyrus granular layer. n = 7 NTG and 8 hAPP mice (a); 3 NTG and 5 hAPP/PS1 mice (b); 1 NTG/7 m, 4 Tau-P301S/3 m and 4 Tau-P301S/6.5 m mice (c); 3 APOE3-KI/6 m, 3 APOE3-KI/19 m, 3 APOE4-KI/6 m, and 3 APOE4-KI/17 m mice (d). Scale bars: 50 μm.

Mentions: Our findings suggest that astrocytic A2A receptors regulate memory in mice and that the levels of these receptors increase in humans with AD. We next investigated the link between AD pathology and astrocytic A2A receptors in AD-related mouse models. Transgenic mice with neuronal expression of familial AD-linked mutant human amyloid precursor protein (hAPP) develop a number of AD-like pathological alterations, including amyloid plaques, neuritic dystrophy, astrocytosis and microgliosis, and show deficits in learning and memory.10, 36, 37 Also similar to humans with AD, we found that plaque-bearing 14–20-month-old hAPP mice from line J20 have increased levels of astrocytic A2A receptor immunoreactivity in the hippocampus as compared to nontransgenic (NTG) littermate controls (Fig. 7a and Supplementary Figs. 9 and 10). The increases in A2A receptor expression were localized to astrocytes, but not microglia, as determined by colabeling for the A2A receptor and cell-selective markers (Fig. 7a and Supplementary Figs. 9 and 10). The most prominent increases in astrocytic A2A receptor expression were found in the vicinity of Thioflavin-S-positive plaques (Supplementary Fig. 9d–e). In contrast to aging hAPP mice, 2–3-month-old hAPP mice have no plaques36 and showed no increases in astrocytic A2A receptor immunoreactivity (Supplementary Fig. 10a).


Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J, Yu GQ, Adame A, Devidze N, Dubal DB, Masliah E, Conklin BR, Mucke L - Nat. Neurosci. (2015)

Astrocytic A2A receptor levels are increased in transgenic mice expressing mutant forms of hAPP alone or in combination with a mutant form of PS1(a–d) Representative photomicrographs of hippocampal sections immunostained for the A2A receptor (green) and the astrocyte marker GFAP (red) from nontransgenic (NTG) mice and from transgenic mice expressing hAPP alone (a) or in combination with a mutant form of PS1 (b), transgenic mice expressing a mutant form of human tau (Tau-P301S) (c), or knock-in mice expressing human apoE3 (APOE3-KI) or apoE4 (ApoE4-KI) (d). Ages of the mice are indicated in months (m, left). Cell nuclei were labeled with DAPI (blue). Insets (i–xi) show magnified views of the boxed regions. DGgl: dentate gyrus granular layer. n = 7 NTG and 8 hAPP mice (a); 3 NTG and 5 hAPP/PS1 mice (b); 1 NTG/7 m, 4 Tau-P301S/3 m and 4 Tau-P301S/6.5 m mice (c); 3 APOE3-KI/6 m, 3 APOE3-KI/19 m, 3 APOE4-KI/6 m, and 3 APOE4-KI/17 m mice (d). Scale bars: 50 μm.
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Figure 7: Astrocytic A2A receptor levels are increased in transgenic mice expressing mutant forms of hAPP alone or in combination with a mutant form of PS1(a–d) Representative photomicrographs of hippocampal sections immunostained for the A2A receptor (green) and the astrocyte marker GFAP (red) from nontransgenic (NTG) mice and from transgenic mice expressing hAPP alone (a) or in combination with a mutant form of PS1 (b), transgenic mice expressing a mutant form of human tau (Tau-P301S) (c), or knock-in mice expressing human apoE3 (APOE3-KI) or apoE4 (ApoE4-KI) (d). Ages of the mice are indicated in months (m, left). Cell nuclei were labeled with DAPI (blue). Insets (i–xi) show magnified views of the boxed regions. DGgl: dentate gyrus granular layer. n = 7 NTG and 8 hAPP mice (a); 3 NTG and 5 hAPP/PS1 mice (b); 1 NTG/7 m, 4 Tau-P301S/3 m and 4 Tau-P301S/6.5 m mice (c); 3 APOE3-KI/6 m, 3 APOE3-KI/19 m, 3 APOE4-KI/6 m, and 3 APOE4-KI/17 m mice (d). Scale bars: 50 μm.
Mentions: Our findings suggest that astrocytic A2A receptors regulate memory in mice and that the levels of these receptors increase in humans with AD. We next investigated the link between AD pathology and astrocytic A2A receptors in AD-related mouse models. Transgenic mice with neuronal expression of familial AD-linked mutant human amyloid precursor protein (hAPP) develop a number of AD-like pathological alterations, including amyloid plaques, neuritic dystrophy, astrocytosis and microgliosis, and show deficits in learning and memory.10, 36, 37 Also similar to humans with AD, we found that plaque-bearing 14–20-month-old hAPP mice from line J20 have increased levels of astrocytic A2A receptor immunoreactivity in the hippocampus as compared to nontransgenic (NTG) littermate controls (Fig. 7a and Supplementary Figs. 9 and 10). The increases in A2A receptor expression were localized to astrocytes, but not microglia, as determined by colabeling for the A2A receptor and cell-selective markers (Fig. 7a and Supplementary Figs. 9 and 10). The most prominent increases in astrocytic A2A receptor expression were found in the vicinity of Thioflavin-S-positive plaques (Supplementary Fig. 9d–e). In contrast to aging hAPP mice, 2–3-month-old hAPP mice have no plaques36 and showed no increases in astrocytic A2A receptor immunoreactivity (Supplementary Fig. 10a).

Bottom Line: Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory.However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known.Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

View Article: PubMed Central - PubMed

Affiliation: 1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.

ABSTRACT
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

Show MeSH
Related in: MedlinePlus