Carvalho K, Faivre E, Pietrowski MJ, Marques X, Gomez-Murcia V, Deleau A, Huin V, Hansen JN, Kozlov S, Danis C, Temido-Ferreira M, Coelho JE, Mériaux C, Eddarkaoui S, Gras SL, Dumoulin M, Cellai L, NeuroCEB Brain Bank, Landrieu I, Chern Y, Hamdane M, Buée L, Boutillier AL, Levi S, Halle A, Lopes LV, Blum D. Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor. Brain. 2019 Nov 1;142(11):3636-3654. PubMed.

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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.

    View all comments by Carlo Sala Frigerio

  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:

    Arendash GW, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, Echeverria V, Potter H. 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.

    Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience. 2006 Nov 3;142(4):941-52. PubMed.

    Cao C, Cirrito JR, Lin X, Wang L, Verges DK, Dickson A, Mamcarz M, Zhang C, Mori T, Arendash GW, Holtzman DM, Potter H. Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer's disease transgenic mice. J Alzheimers Dis. 2009;17(3):681-97. PubMed.

    Cao C, Loewenstein DA, Lin X, Zhang C, Wang L, Duara R, Wu Y, Giannini A, Bai G, Cai J, Greig M, Schofield E, Ashok R, Small B, Potter H, Arendash GW. High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia. J Alzheimers Dis. 2012 Jan 1;30(3):559-72. PubMed.

    Temido-Ferreira M, Ferreira DG, Batalha VL, Marques-Morgado I, Coelho JE, Pereira P, Gomes R, Pinto A, Carvalho S, Canas PM, Cuvelier L, Buée-Scherrer V, Faivre E, Baqi Y, Müller CE, Pimentel J, Schiffmann SN, Buée L, Bader M, Outeiro TF, Blum D, Cunha RA, Marie H, Pousinha PA, Lopes LV. Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors. Mol Psychiatry. 2018 Jun 27; PubMed.

    Faivre E, Coelho JE, Zornbach K, Malik E, Baqi Y, Schneider M, Cellai L, Carvalho K, Sebda S, Figeac M, Eddarkaoui S, Caillierez R, Chern Y, Heneka M, Sergeant N, Müller CE, Halle A, Buée L, Lopes LV, Blum D. 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.

    View all comments by Huntington Potter

  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:

    Canas PM, Porciúncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, Oliveira CR, Cunha RA. 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.

    Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendonça A. 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.

    Laurent C, Burnouf S, Ferry B, Batalha VL, Coelho JE, Baqi Y, Malik E, Marciniak E, Mariciniak E, Parrot S, Van der Jeugd A, Faivre E, Flaten V, Ledent C, D'Hooge R, Sergeant N, Hamdane M, Humez S, Müller CE, Lopes LV, Buée L, Blum D. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry. 2016 Jan;21(1):149. Epub 2015 Jul 28 PubMed.

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

    Orr AG, Lo I, Schumacher H, Ho K, Gill M, Guo W, Kim DH, Knox A, Saito T, Saido TC, Simms J, Toddes C, Wang X, Yu GQ, Mucke L. Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis. 2018 Feb;110:29-36. Epub 2017 Oct 31 PubMed.

    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA. A Dramatic Increase of C1q Protein in the CNS during Normal Aging. J Neurosci. 2013 Aug 14;33(33):13460-74. PubMed.

    Viana da Silva S, Haberl MG, Zhang P, Bethge P, Lemos C, Gonçalves N, Gorlewicz A, Malezieux M, Gonçalves FQ, Grosjean N, Blanchet C, Frick A, Nägerl UV, Cunha RA, Mulle C. 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.

    View all comments by Anna Orr

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News

  1. Adenosine Receptors Rev Up Immune Response, Memory Loss, in Tau Model

Mutations

  1. MAPT P301L