Adenosine receptors may hasten inflammatory responses to tau pathology, according to a paper published this month in Brain. Researchers led by David Blum of the University of Lille, France, reported that in a mouse model of tauopathy, the adenosine-2A receptors exacerbated tau phosphorylation and memory loss. Though the researchers overexpressed the receptors in neurons, the A2ARs triggered a response in microglia, namely an uptick in inflammatory genes, including the complement protein C1q that has been linked to synaptic pruning in this tauopathy models. The researchers also found more A2A receptors in brains of people who had died with frontotemporal dementia than in healthy controls.

  • Adenosine-2A receptor overexpression in a tau mouse model hastened memory loss and synaptic damage.
  • People with FTD had more A2A receptors in the frontal cortex.
  • The receptors upped expression of microglial genes TREM2 and C1q.

Best known for binding caffeine, adenosine receptors—of which A1, A2A, A2B, and A3 varieties exist—have been implicated in multiple types of neurodegeneration (for review, see Cunha, 2016). Blum’s group previously reported that deleting or blocking the A2A receptor lessened tau hyperphosphorylation and neuroinflammation, spared synaptic function, and rescued memory deficits in Thy-Tau22 mice, which express the P301S mutant form of human tau (Laurent et al., 2014). 

Subsequently, the scientists blocked the receptor in APP/PS1 mice and found less amyloid and memory loss (Faivre et al., 2018). Other groups deleted A2AR in astrocytes in both normal and AD model mice and reported improved memory (Dec 2014 newsJan 2015 news). In humans, brain adenosine receptors reportedly rise with age, and more so in people with AD (Temido-Ferreira et al., 2018). 

In the current study, first author Kevin Carvalho and colleagues asked if adenosine receptor expression might crank up in a pure tauopathy. Indeed, according to western blots, they found around twice as much A2AR protein in brain extracts from three people with frontotemporal dementia who carried the P301L mutation, than in extracts from three age-matched controls. Immunostaining tissue sections revealed about 25 percent more A2AR in neurons burdened with tau pathology than in those without (see image below).

A2AR in FTD. Immunohistochemistry (left) indicated more A2AR expression (red) in FTD than in control brains. A2AR levels were higher in neurons with tau pathology (arrows) than in those without (asterisks). Relative fluorescence of A2AR staining is plotted on right. [Courtesy of Carvalho et al., Brain, 2019.]

To examine if this elevated A2AR expression might exacerbate the progression of tauopathy, the researchers generated a mouse model in which they could induce overexpression of A2AR in forebrain neurons, then crossed it to the Thy-Tau22 strain. When the A2AR transgene was overexpressed at around one month of age, spatial memory deficits appeared four to five months later. ThyTau22 mice typically start having memory problems around nine months of age. The authors did not keep any A2AR/Tau22 mice on doxycycline for that long. Turning on A2AR also boosted phosphorylation of hippocampal tau at some residues, but not others. Other regions of the forebrain were not assessed for comparison.

To investigate how A2AR might hasten the memory slide, the researchers measured RNA levels in the hippocampi of 6-month-old mice. At this age, Tau22 or A2AR mice did not differ substantially from controls, but Tau22/A2AR mice did. They had 505 differentially expressed genes, of which 441 were downregulated. Most of those function in RNA metabolism, whereas most of the 64 upregulated genes are involved in immune processes. Of the 64, 54 are annotated in the RNA-seq database developed by the late Ben Barres (Zhang et al., 2014). According to this database, 33 of the genes are microglial. They include Trem2, Csf1r, and the complement protein C1qa. Levels of RNA for C1qb and C1qc, the two other proteins that make up the C1q complex, trended toward higher expression.

Investigating the C1q uptick, the researchers found significantly higher protein levels of the C1q complex in Tau22/A2AR mice, particularly in the molecular layer of the dentate gyrus. In keeping with the idea that complement tags synapses for destruction, glutamatergic synapses appeared sparse in this region. In Thy-Tau22 mice with normal A2AR expression, C1q levels rose at 9 months of age, coinciding with the first inkling of synaptic deficits and memory loss.

Looking in human brain samples, the researchers found that A2AR correlated with C1q levels in the frontal cortices of people with P301L FTD, as well as in those without the mutation who had corticobasal syndrome or Pick’s disease, two related tauopathies.

Blum believes that A2AR signaling mediates communication between neurons and glia. Though it is unclear why A2AR expression rises in tauopathies, Blum thinks it somehow trips inflammatory responses in glial cells, including the complement cascade, which erodes synapses and causes memory problems. He suspects the same could be true in multiple neurodegenerative diseases.

“The findings reinforce the idea that there is crosstalk between neuronal functions (e.g. oscillations) and the brain immune system, with potential consequences under pathological conditions,” wrote Marc Aurel Busche and Carlo Sala Frigerio of University College London in a joint comment to Alzforum. Future research should focus on what ramps up A2AR in aging and disease, and how this influences glia. “The study also raises the important question of whether—and how—antagonism of A2A receptors (e.g. through caffeine) could have a disease-modifying effect in patients,” they wrote.

Blum told Alzforum that he has initiated a clinical trial testing caffeine as a treatment for cognitive decline in people with mild to moderate AD. The multicenter, placebo-controlled trial will start enrolling participants in Northern France in January 2020, and will test the efficacy of a 400 mg daily dose of caffeine to curb slippage on the neuropsychological test battery over 30 weeks. All participants will be asked to give up their own caffeine starting six weeks prior to the treatment phase.—Jessica Shugart

Comments

  1. This is an intriguing paper showing that abnormal upregulation of neuronal A2A receptors accelerates tau pathology and spatial memory impairment in a tau model. Of particular interest is the demonstration that an abnormal neuronal phenotype is able to trigger molecular changes in microglia, which are shown to upregulate the expression of several genes, including Csf1r, Trem2, and members of the C1q family. Curiously, this is not accompanied by changes in microglial number or morphology. The finding reinforces the idea that there is crosstalk between neuronal functions (e.g. oscillations) and the brain immune system, with potential consequences under pathological conditions. Indeed, C1q has been proposed to tag synapses for removal, and an increase in its expression could result in pathological overpruning of synapses.

    It is not clear how A2A receptor overexpression alters neuronal function in the context of tauopathy, and how this subsequently impacts microglia. Further, it is not known what triggers A2AR overexpression in aged subjects and individuals with Alzheimer’s disease or tauopathy. Elucidating these important questions in future work will be crucial to understanding the clinical relevance of the findings.

    It is well known that neuronal (and astrocytic) A2A receptors increase in response to epilepsy and other brain injuries (e.g., traumatic brain injury), and that this upregulation could be a plausible intermediate or contributor to the accelerated disease progression (i.e., earlier age of onset of symptoms) frequently observed in patients with those comorbidities. This study also raises the important question of whether—and how—antagonism of A2A receptors (e.g., through caffeine) could have a disease-modifying effect in patients.

  2. Better Than Coffee: A More Specific Adenosine A2A Receptor Antagonist Shows Preclinical Promise Against Neurodegeneration in Alzheimer’s Disease and Other Tauopathies

    This team led by Dr. David Blum has been pursuing specific adenosine A2A receptor (A2AR) antagonists as potential treatments for Alzheimer’s disease. Previous work from our lab and others showed that caffeine, a non-specific antagonist of A2AR, reduced brain Aβ formation and both prevented and reduced amyloid load and cognitive decline in mouse models of AD, inhibited both Aβ peptide formation and GSK3 kinase activity in cell culture, and, when present in high levels in plasma, predicted which subjects with mild cognitive impairment would not convert to AD by their three-year follow-up visit (Arendash et al., 2009; Arendash et al., 2006; Cao et al., 2009; Cao et al., 2012). 

    Blum and colleagues have shown that the A2AR is upregulated in hippocampal neurons from aged individuals and is exacerbated in AD subjects (Temido-Ferreira et al., 2018), and that treatment with the specific A2AR antagonist MSX-3 can reduce the Aβ42/40 ratio and amyloid plaques in the cortex and prevent spatial memory impairment in APPswe/PS1dE9 double transgenic mice (Faivre et al., 2018). 

    In this report, they showed that A2AR levels are also increased in brains of frontotemporal lobar degeneration (FTLD) subjects carrying a P301L mutation, which results in a pure tauopathy, and that conditional forebrain-specific upregulation of A2AR expression in the THY-Tau22 tauopathy model results in increased levels of tau hyperphosphorylation and promotes memory deficits. Furthermore, expression analysis revealed a singular microglial signature, including upregulation of complement component C1q, in the hippocampus, which may explain the downregulation of glutaminergic synapses and cognitive deficits. These results pave the way for MSX-3 or other A2AR antagonists as potential treatments for FTLD and possibly for other tauopathies in addition to AD.

    References:

    . Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice. J Alzheimers Dis. 2009;17(3):661-80. PubMed.

    . Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006 Nov 3;142(4):941-52. PubMed.

    . Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer's disease transgenic mice. J Alzheimers Dis. 2009;17(3):681-97. PubMed.

    . High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia. J Alzheimers Dis. 2012 Jan 1;30(3):559-72. PubMed.

    . Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors. Mol Psychiatry. 2018 Jun 27; PubMed.

    . Beneficial Effect of a Selective Adenosine A2A Receptor Antagonist in the APPswe/PS1dE9 Mouse Model of Alzheimer's Disease. Front Mol Neurosci. 2018;11:235. Epub 2018 Jul 12 PubMed.

  3. Adenosine A2A receptors play key roles in neurological disease and might be promising therapeutic targets for dementia‐ related cognitive decline. However, the exact mechanisms underlying the effects of A2A receptors in disease are unclear.

    Here, Carvalho et al. report that overexpression of A2A receptors specifically in forebrain neurons accelerates the onset of tauopathy, synaptic loss, glial alterations, and memory deficits in young transgenic mice expressing mutant tau. These intriguing results suggest that neuronal A2A is a contributing factor in tau‐associated pathology, and are consistent with previous studies by this group and others demonstrating the detrimental roles of A2A expression and activity in AD‐ associated pathology and cognitive decline.

    It is interesting that neuronal A2A overexpression was sufficient to induce memory loss even in the absence of mutant tau, but it only induced synaptic loss and immune‐related genes such as C1q in the presence of mutant tau. These results support previous observations that the effects of A2A are context‐dependent and may impair neural function by different mechanisms. Our previous work on astrocytic A2A receptors further highlights the diverse cell‐specific effects of A2A receptors that are likely important in health and disease. It would be interesting to dissect how gene expression patterns change in specific cell types when A2A is manipulated in different cell populations, and the effects of such manipulations at older ages, when the expression of C1q is increasing and aging‐related memory deficits are emerging.

    Notably, in August of this year, the FDA approved the use of an A2A receptor antagonist istradefylline (Nourianz) as an adjunct treatment for motor symptoms in patients with Parkinson’s disease. Given that A2A antagonists reduce memory deficits in diverse animal models, it will be imperative to test if istradefylline and other A2A blockers can counteract memory loss in patients with AD and related dementias.

    References:

    . Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci. 2009 Nov 25;29(47):14741-51. PubMed.

    . Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation. Prog Neurobiol. 2007 Dec;83(5):310-31. PubMed.

    . A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry. 2016 Jan;21(1):149. Epub 2015 Jul 28 PubMed.

    . Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci. 2015 Mar;18(3):423-34. Epub 2015 Jan 26 PubMed.

    . Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis. 2018 Feb;110:29-36. Epub 2017 Oct 31 PubMed.

    . A Dramatic Increase of C1q Protein in the CNS during Normal Aging. J Neurosci. 2013 Aug 14;33(33):13460-74. PubMed.

    . Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors. Nat Commun. 2016 Jun 17;7:11915. PubMed.

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References

Research Models Citations

  1. THY-Tau22
  2. APPswe/PSEN1dE9 (line 85)

News Citations

  1. Do Astrocyte Receptors Go Over the Top in Alzheimer’s?
  2. Paper Alert: Astrocyte Receptor Could Hinder Memory

Paper Citations

  1. . How does adenosine control neuronal dysfunction and neurodegeneration?. J Neurochem. 2016 Dec;139(6):1019-1055. Epub 2016 Aug 16 PubMed.
  2. . A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry. 2014 Dec 2; PubMed.
  3. . Beneficial Effect of a Selective Adenosine A2A Receptor Antagonist in the APPswe/PS1dE9 Mouse Model of Alzheimer's Disease. Front Mol Neurosci. 2018;11:235. Epub 2018 Jul 12 PubMed.
  4. . Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors. Mol Psychiatry. 2018 Jun 27; PubMed.
  5. . An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014 Sep 3;34(36):11929-47. PubMed.

External Citations

  1. RNA-seq database

Further Reading

Primary Papers

  1. . Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptors. Brain, October 2019