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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 expression is increased in humans with AD(a) Levels of A2A receptor protein in hippocampi (HP) and frontal cortices (FC) of human control (Con) and AD cases as determined by western blotting. Ratios of A2A/actin were normalized to the average ratio in Con samples. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.001 (HP); P = 0.70 (FC). n = 5 (Con HP), 17 (AD HP), 5 (Con FC), and 16 (AD FC) cases per group. (b) Levels of ADORA2A and GFAP mRNA in the dentate gyri from Con and AD cases as determined by qRT-PCR. GAPDH mRNA served as a loading control. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.0008 (ADORA2A); P < 0.0001 (GFAP). n = 3 (Con ADORA2A), 15 (AD ADORA2A), 3 (Con GFAP), and 16 (AD GFAP) cases per group. (c) Levels of ADORA2A mRNA in the dentate gyri of humans with AD ranging from mild to severe based on pathological analysis and Braak scoring.12ADORA2A/GAPDH ratios were plotted as a function of Braak score. Spearman rank correlation, R = 0.76, P = 0.0063, n = 11 cases. Red line shows the linear regression curve and dotted lines show the 95% confidence intervals. (d) Levels of ADORA2A mRNA in the dentate gyri of humans with AD plotted as a function of GFAP mRNA levels. Spearman rank correlation, R = 0.57, P = 0.027, n = 15 cases. GAPDH mRNA served as a loading control. (e–f) Representative photomicrographs of A2A receptor immunoreactivity in hippocampal sections from two independent cohorts of human cases with the indicated Braak stages. Severity of cognitive impairment is indicated by Mini Mental State Examination (MMSE) or Blessed Dementia Scale (BDS) scores. Insets (i–iv) show magnified views of the boxed regions. (g) Representative photomicrographs of a hippocampal section from an AD case co-immunostained for the A2A receptor (green) and the astrocyte marker Aldh1L1 (red). Cell nuclei were labeled with DAPI (blue). The overlay shows co-localization of A2A and Aldh1L1 immunoreactivities. Scale bars: 100 μm (e–g), 25 μm (bottom insets in g). n = 10 Con and 19 AD cases. Insets (i–vi) show magnified views of the boxed regions. ***P < 0.001 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.
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Figure 1: Astrocytic A2A receptor expression is increased in humans with AD(a) Levels of A2A receptor protein in hippocampi (HP) and frontal cortices (FC) of human control (Con) and AD cases as determined by western blotting. Ratios of A2A/actin were normalized to the average ratio in Con samples. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.001 (HP); P = 0.70 (FC). n = 5 (Con HP), 17 (AD HP), 5 (Con FC), and 16 (AD FC) cases per group. (b) Levels of ADORA2A and GFAP mRNA in the dentate gyri from Con and AD cases as determined by qRT-PCR. GAPDH mRNA served as a loading control. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.0008 (ADORA2A); P < 0.0001 (GFAP). n = 3 (Con ADORA2A), 15 (AD ADORA2A), 3 (Con GFAP), and 16 (AD GFAP) cases per group. (c) Levels of ADORA2A mRNA in the dentate gyri of humans with AD ranging from mild to severe based on pathological analysis and Braak scoring.12ADORA2A/GAPDH ratios were plotted as a function of Braak score. Spearman rank correlation, R = 0.76, P = 0.0063, n = 11 cases. Red line shows the linear regression curve and dotted lines show the 95% confidence intervals. (d) Levels of ADORA2A mRNA in the dentate gyri of humans with AD plotted as a function of GFAP mRNA levels. Spearman rank correlation, R = 0.57, P = 0.027, n = 15 cases. GAPDH mRNA served as a loading control. (e–f) Representative photomicrographs of A2A receptor immunoreactivity in hippocampal sections from two independent cohorts of human cases with the indicated Braak stages. Severity of cognitive impairment is indicated by Mini Mental State Examination (MMSE) or Blessed Dementia Scale (BDS) scores. Insets (i–iv) show magnified views of the boxed regions. (g) Representative photomicrographs of a hippocampal section from an AD case co-immunostained for the A2A receptor (green) and the astrocyte marker Aldh1L1 (red). Cell nuclei were labeled with DAPI (blue). The overlay shows co-localization of A2A and Aldh1L1 immunoreactivities. Scale bars: 100 μm (e–g), 25 μm (bottom insets in g). n = 10 Con and 19 AD cases. Insets (i–vi) show magnified views of the boxed regions. ***P < 0.001 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.

Mentions: We found increased levels of A2A receptor protein in the hippocampal formation, but not frontal cortex, of humans with AD as compared to aged controls (Fig. 1a and Supplementary Table 1). Although increased A2A receptor ligand binding has been reported in the frontal cortex of AD patients, the levels of A2A receptor protein and mRNA in this region were not altered,8 consistent with our findings. ADORA2A mRNA levels in the dentate gyrus of AD patients were also increased and strongly correlated with AD pathology as classified by the Braak score,12 a measure of neurofibrillary tangles and disease progression (Fig. 1b–c; Spearman rank correlation, R = 0.76, P = 0.0063, n = 11 cases). ADORA2A mRNA levels correlated also with the levels of mRNA encoding glial fibrillary acidic protein (GFAP), a marker of astrogliosis (Fig. 1d; Spearman rank correlation, R = 0.57, P = 0.027, n = 15 cases).


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 expression is increased in humans with AD(a) Levels of A2A receptor protein in hippocampi (HP) and frontal cortices (FC) of human control (Con) and AD cases as determined by western blotting. Ratios of A2A/actin were normalized to the average ratio in Con samples. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.001 (HP); P = 0.70 (FC). n = 5 (Con HP), 17 (AD HP), 5 (Con FC), and 16 (AD FC) cases per group. (b) Levels of ADORA2A and GFAP mRNA in the dentate gyri from Con and AD cases as determined by qRT-PCR. GAPDH mRNA served as a loading control. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.0008 (ADORA2A); P < 0.0001 (GFAP). n = 3 (Con ADORA2A), 15 (AD ADORA2A), 3 (Con GFAP), and 16 (AD GFAP) cases per group. (c) Levels of ADORA2A mRNA in the dentate gyri of humans with AD ranging from mild to severe based on pathological analysis and Braak scoring.12ADORA2A/GAPDH ratios were plotted as a function of Braak score. Spearman rank correlation, R = 0.76, P = 0.0063, n = 11 cases. Red line shows the linear regression curve and dotted lines show the 95% confidence intervals. (d) Levels of ADORA2A mRNA in the dentate gyri of humans with AD plotted as a function of GFAP mRNA levels. Spearman rank correlation, R = 0.57, P = 0.027, n = 15 cases. GAPDH mRNA served as a loading control. (e–f) Representative photomicrographs of A2A receptor immunoreactivity in hippocampal sections from two independent cohorts of human cases with the indicated Braak stages. Severity of cognitive impairment is indicated by Mini Mental State Examination (MMSE) or Blessed Dementia Scale (BDS) scores. Insets (i–iv) show magnified views of the boxed regions. (g) Representative photomicrographs of a hippocampal section from an AD case co-immunostained for the A2A receptor (green) and the astrocyte marker Aldh1L1 (red). Cell nuclei were labeled with DAPI (blue). The overlay shows co-localization of A2A and Aldh1L1 immunoreactivities. Scale bars: 100 μm (e–g), 25 μm (bottom insets in g). n = 10 Con and 19 AD cases. Insets (i–vi) show magnified views of the boxed regions. ***P < 0.001 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.
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Figure 1: Astrocytic A2A receptor expression is increased in humans with AD(a) Levels of A2A receptor protein in hippocampi (HP) and frontal cortices (FC) of human control (Con) and AD cases as determined by western blotting. Ratios of A2A/actin were normalized to the average ratio in Con samples. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.001 (HP); P = 0.70 (FC). n = 5 (Con HP), 17 (AD HP), 5 (Con FC), and 16 (AD FC) cases per group. (b) Levels of ADORA2A and GFAP mRNA in the dentate gyri from Con and AD cases as determined by qRT-PCR. GAPDH mRNA served as a loading control. Student’s t-test with Welch’s correction (Con vs. AD): P = 0.0008 (ADORA2A); P < 0.0001 (GFAP). n = 3 (Con ADORA2A), 15 (AD ADORA2A), 3 (Con GFAP), and 16 (AD GFAP) cases per group. (c) Levels of ADORA2A mRNA in the dentate gyri of humans with AD ranging from mild to severe based on pathological analysis and Braak scoring.12ADORA2A/GAPDH ratios were plotted as a function of Braak score. Spearman rank correlation, R = 0.76, P = 0.0063, n = 11 cases. Red line shows the linear regression curve and dotted lines show the 95% confidence intervals. (d) Levels of ADORA2A mRNA in the dentate gyri of humans with AD plotted as a function of GFAP mRNA levels. Spearman rank correlation, R = 0.57, P = 0.027, n = 15 cases. GAPDH mRNA served as a loading control. (e–f) Representative photomicrographs of A2A receptor immunoreactivity in hippocampal sections from two independent cohorts of human cases with the indicated Braak stages. Severity of cognitive impairment is indicated by Mini Mental State Examination (MMSE) or Blessed Dementia Scale (BDS) scores. Insets (i–iv) show magnified views of the boxed regions. (g) Representative photomicrographs of a hippocampal section from an AD case co-immunostained for the A2A receptor (green) and the astrocyte marker Aldh1L1 (red). Cell nuclei were labeled with DAPI (blue). The overlay shows co-localization of A2A and Aldh1L1 immunoreactivities. Scale bars: 100 μm (e–g), 25 μm (bottom insets in g). n = 10 Con and 19 AD cases. Insets (i–vi) show magnified views of the boxed regions. ***P < 0.001 (Student’s t-test with Welch’s correction). Values are means ± s.e.m.
Mentions: We found increased levels of A2A receptor protein in the hippocampal formation, but not frontal cortex, of humans with AD as compared to aged controls (Fig. 1a and Supplementary Table 1). Although increased A2A receptor ligand binding has been reported in the frontal cortex of AD patients, the levels of A2A receptor protein and mRNA in this region were not altered,8 consistent with our findings. ADORA2A mRNA levels in the dentate gyrus of AD patients were also increased and strongly correlated with AD pathology as classified by the Braak score,12 a measure of neurofibrillary tangles and disease progression (Fig. 1b–c; Spearman rank correlation, R = 0.76, P = 0.0063, n = 11 cases). ADORA2A mRNA levels correlated also with the levels of mRNA encoding glial fibrillary acidic protein (GFAP), a marker of astrogliosis (Fig. 1d; Spearman rank correlation, R = 0.57, P = 0.027, n = 15 cases).

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