Adenosine Receptors in Alzheimer’s Disease

  • Paula M. Canas
  • Rodrigo A. Cunha
  • Paula AgostinhoEmail author
Part of the The Receptors book series (REC, volume 34)


Adenosine operates its effects through adenosine receptors, which have been proposed to be of particular relevance in neuropathological situations, such as Alzheimer’s disease (AD). AD is characterized by progressive cognitive impairment, synaptic and neuronal loss, formation of amyloid plaques, mainly composed by amyloid-beta (Aβ) peptides, and neurofibrillary tangles as well as neuroinflammation. Epidemiological studies concluded that the regular consumption of caffeine, a nonselective antagonist of adenosine receptors, is inversely correlated with the incidence of AD. Neurochemical data showed an increased A2AR density in the brain of AD patients, and these A2ARs interfere with memory, synaptic plasticity, Aβ production and neurofibrillary tangles formation in AD models. Accordingly, pharmacological blockade or genetic inactivation of A2AR prevents cognitive impairment and affords neuroprotection. However, either the mechanisms or the contribution of A2AR in different cell types for the onset and progression of AD are not completely understood. Until now, it was described that neuronal and astrocytic A2ARs have a role in controlling synaptic plasticity and memory, microglial A2AR modulates neuroinflammation and A2AR in peripheral cells also comes into play in neurodegenerative processes. This chapter will discuss the importance of adenosinergic system in AD patients and experimental models, providing an overview of future adenosine-based therapies.


Adenosine receptors Alzheimer’s disease Amyloid-beta Neuroinflammation Caffeine 



The authors ‘research was supported by Maratona da Saúde, the European Regional Development Fund (ERDF) through the COMPETE 2020 and Portuguese National Funds (FCT), ref POCI-01-0145-FEDER-007440 and PTDC/NEU-NMC/4154/2014 - AstroA2AR (POCI-01-0145-FEDER-016684).


  1. Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer’s disease. Curr Pharm Des 16:2766–2778PubMedCrossRefPubMedCentralGoogle Scholar
  2. Agostinho P, Pliássova A, Oliveira CR et al (2015) Localization and trafficking of amyloid-β protein precursor and secretases: impact on Alzheimer’s disease. J Alzheimers Dis 45:329–347PubMedCrossRefPubMedCentralGoogle Scholar
  3. Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421PubMedPubMedCentralCrossRefGoogle Scholar
  4. Albasanz JL, Perez S, Barrachina M et al (2008) Up-regulation of adenosine receptors in the frontal cortex in Alzheimer’s disease. Brain Pathol 18:211–219PubMedCrossRefGoogle Scholar
  5. Allaman I, Lengacher S, Magistretti PJ et al (2003) A2B receptor activation promotes glycogen synthesis in astrocytes through modulation of gene expression. Am J Phys 284:C696–C704CrossRefGoogle Scholar
  6. Angulo E, Casado V, Mallol J et al (2003) A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. Brain Pathol 13:440–451PubMedCrossRefPubMedCentralGoogle Scholar
  7. Arendash GW, Schleif W, Rezai-Zadeh K et al (2006) Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience 142:941–952PubMedCrossRefGoogle Scholar
  8. Arendash GW, Mori T, Cao C et al (2009) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer’s disease mice. J Alzheimers Dis 17:661–680PubMedCrossRefPubMedCentralGoogle Scholar
  9. Batalha VL, Ferreira DG, Coelho JE et al (2016) The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function. Sci Rep 6:31493PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bertram L, Tanzi RE (2004) Alzheimer’s disease: one disorder, too many genes? Hum Mol Genet 13:R135–R141PubMedCrossRefPubMedCentralGoogle Scholar
  11. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403PubMedPubMedCentralCrossRefGoogle Scholar
  12. Blennow K, Hampel H, Weiner M et al (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144PubMedCrossRefPubMedCentralGoogle Scholar
  13. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bramblett GT, Goedert M, Jakes R et al (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10:1089–1099PubMedCrossRefPubMedCentralGoogle Scholar
  15. Burckhardt M, Herke M, Wustmann T et al (2016) Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev 4:CD009002Google Scholar
  16. Burnstock G, Fredholm BB, Verkhratsky A (2011) Adenosine and ATP receptors in the brain. Curr Top Med Chem 11:973–1011PubMedCrossRefPubMedCentralGoogle Scholar
  17. Canas PM, Duarte JM, Rodrigues RJ et al (2009a) Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol Aging 30:1877–1884PubMedCrossRefGoogle Scholar
  18. Canas PM, Porciúncula LO, Cunha GM et al (2009b) Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 29:14741–14751PubMedCrossRefGoogle Scholar
  19. Cao C, Cirrito JR, Lin X et al (2009) Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer’s disease transgenic mice. J Alzheimers Dis 17:681–697PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cao C, Loewenstein DA, Lin X et al (2012) High blood caffeine levels in MCI linked to lack of progression to dementia. J Alzheimers Dis 30:559–572PubMedPubMedCentralCrossRefGoogle Scholar
  21. Carman AJ, Mills JH, Krenz A et al (2011) Adenosine receptor signaling modulates permeability of the blood-brain barrier. J Neurosci 31:13272–13280PubMedPubMedCentralCrossRefGoogle Scholar
  22. Castillo CA, Albasanz JL, Leon D et al (2009) Age-related expression of adenosine receptors in brain from the senescence-accelerated mouse. Exp Gerontol 44:453–461PubMedCrossRefPubMedCentralGoogle Scholar
  23. Chen JF (2014) Adenosine receptor control of cognition in normal and disease. Int Rev Neurobiol 119:257–307PubMedCrossRefPubMedCentralGoogle Scholar
  24. Chen Z, Zhong C (2013) Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 108:21–43PubMedCrossRefPubMedCentralGoogle Scholar
  25. Chen GJ, Harvey BK, Shen H et al (2006) Activation of adenosine A3 receptors reduces ischemic brain injury in rodents. J Neurosci Res 84:1848–1855PubMedCrossRefPubMedCentralGoogle Scholar
  26. Cheng J, Liu I, Juang S et al (2000) Decrease of adenosine A-1 receptor gene expression in cerebral cortex of aged rats. Neurosci Lett 283:227–229PubMedCrossRefPubMedCentralGoogle Scholar
  27. Ciruela F, Casadó V, Rodrigues RJ et al (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci 26:2080–2087PubMedCrossRefPubMedCentralGoogle Scholar
  28. Citron M, Diehl TS, Gordon G et al (1996) Evidence that the 42- and 40-amino acid forms of amyloid β protein are generated from the β-amyloid precursor protein by different proteas activities. PNAS 93:13170–13175PubMedCrossRefPubMedCentralGoogle Scholar
  29. Cognato GP, Agostinho PM Hockemeyer J et al (2010) Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life. J Neurochem 112:453–462PubMedCrossRefGoogle Scholar
  30. Costenla AR, Diógenes MJ, Canas PM et al (2011) Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing. Eur J Neurosci 34:12–21PubMedCrossRefGoogle Scholar
  31. Crous-Bou M, Minguillón C, Gramunt N et al (2017) Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimers Res Ther 9:71PubMedPubMedCentralCrossRefGoogle Scholar
  32. Cunha RA (2016) How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 139:1019–1055PubMedCrossRefPubMedCentralGoogle Scholar
  33. Cunha RA, Agostinho PM (2010) Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis 20(Suppl 1):S95–116Google Scholar
  34. Cunha RA, Constantino MC, Sebastião AM et al (1995) Modification of A1 and A2A adenosine receptor binding in aged striatum, hippocampus and cortex of the rat. Neuroreport 6:1583–1588PubMedCrossRefGoogle Scholar
  35. Cunha GM, Canas PM, Melo C et al (2008) Adenosine A2A receptor blockade prevents memory dysfunction caused by beta-amyloid peptides but not by scopolamine or MK-801. Exp Neurol 210:776–781PubMedCrossRefGoogle Scholar
  36. Dall’Igna OP, Porciúncula LO, Souza DO et al (2003) Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br J Pharmacol 138:1207–1209PubMedCrossRefGoogle Scholar
  37. Dall’Igna OP, Fett P, Gomes MW et al (2007) Caffeine and adenosine A2A receptor antagonists prevent beta-amyloid25-35-induced cognitive deficits in mice. Exp Neurol 203:241–245PubMedCrossRefGoogle Scholar
  38. de Mendonça A, Sebastião AM, Ribeiro JA (2000) Adenosine: does it have a neuroprotective role after all? Brain Res Rev 33:258–274PubMedCrossRefGoogle Scholar
  39. De Strooper B, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164:603–615Google Scholar
  40. Deckert J, Abel F, Künig G et al (1998) Loss of human hippocampal adenosine A1 receptors in dementia: evidence for lack of specificity. Neurosci Lett 244:1–4PubMedCrossRefGoogle Scholar
  41. Dennissen FJ, Anglada-Huguet M, Sydow A et al (2016) Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human tau DeltaK280. PNAS 113:11597–11602PubMedCrossRefGoogle Scholar
  42. Dickerson BC, Sperling RA (2009) Large-scale functional brain network abnormalities in Alzheimer’s disease: insights from functional neuroimaging. Behav Neurol 21:63–75PubMedPubMedCentralCrossRefGoogle Scholar
  43. Dragicevic N, Delic V, Cao C et al (2012) Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer’s mice and cells. Neuropharmacology 63:1368–1379PubMedCrossRefGoogle Scholar
  44. Duarte JM, Agostinho PM, Carvalho RA et al (2012) Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10/LTJ mice. PLoS One 7:e21899PubMedPubMedCentralCrossRefGoogle Scholar
  45. Dubois B, Feldman HH, Jacova C et al (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127PubMedCrossRefGoogle Scholar
  46. Elman JA, Oh H, Madison CM et al (2014) Neural compensation in older people with brain β-amyloid deposition. Nat Neurosci 17:1316–1318PubMedPubMedCentralCrossRefGoogle Scholar
  47. Espinosa J, Rocha A, Nunes F et al (2013) Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia. J Alzheimers Dis 34:509–518PubMedCrossRefGoogle Scholar
  48. Flaten V, Laurent C, Coelho JE et al (2014) From epidemiology to pathophysiology: what about caffeine in Alzheimer’s disease? Biochem Soc Trans 42:587–592PubMedPubMedCentralCrossRefGoogle Scholar
  49. Fredholm BB, Bättig K, Holmén J et al (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133PubMedGoogle Scholar
  50. Fredholm BB, Chen JF, Cunha RA et al (2005) Adenosine and brain function. Int Rev Neurobiol 63:191–270PubMedCrossRefGoogle Scholar
  51. Freedman ND, Park Y, Abnet CC et al (2012) Association of coffee drinking with total and cause-specific mortality. N Engl J Med 366:1891–1904PubMedPubMedCentralCrossRefGoogle Scholar
  52. Fukumitsu N, Ishii K, Kimura Y et al (2008) Adenosine A1 receptors using 8-dicyclopropylmethyl-1-[(11)C]methyl-3-propylxanthine PET in Alzheimer's disease. Ann Nucl Med 22:841–847Google Scholar
  53. Galvão J, Elvas F, Martins T et al (2015) Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration. Exp Eye Res 140:65–74PubMedCrossRefGoogle Scholar
  54. Gomes CV, Kaster MP, Tomé AR et al (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808:1380–1399PubMedCrossRefGoogle Scholar
  55. Gómez-Isla T, Hollister R, West H et al (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24PubMedCrossRefGoogle Scholar
  56. Gussago C, Arosio B, Casati M et al (2014) Different adenosine A2A receptor expression in peripheral cells from elderly patients with vascular dementia and Alzheimer’s disease. J Alzheimers Dis 40:45–49PubMedCrossRefGoogle Scholar
  57. Gyoneva S, Swanger SA, Zhang J et al (2016) Altered motility of plaque-associated microglia in a model of Alzheimer’s disease. Neuroscience 330:410–420PubMedPubMedCentralCrossRefGoogle Scholar
  58. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185PubMedCrossRefGoogle Scholar
  59. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  60. Hooijmans CR, Pasker-de Jong PC, de Vries RB et al (2012) The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer’s pathology in animal models of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 28:191–209PubMedCrossRefGoogle Scholar
  61. Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148:1204–1222PubMedPubMedCentralCrossRefGoogle Scholar
  62. Hyman BT, Van Hoesen GW, Damasio AR et al (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225:1168–1170PubMedCrossRefPubMedCentralGoogle Scholar
  63. Irwin DJ, Cohen TJ, Grossman M et al (2012) Acetylated tau, a novel pathological signature in Alzheimer’s disease and other tauopathies. Brain 135:807–818PubMedPubMedCentralCrossRefGoogle Scholar
  64. Jacobson KA, von Lubitz DKJE, Daly JW et al (1996) Adenosine receptor ligands: differences with acute versus chronic treatment. Trends Pharmacol Sci 17:108–113PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kalaria RN, Sromek S, Wilcox BJ et al (1990) Hippocampal adenosine A1 receptors are decreased in Alzheimer’s disease. Neurosci Lett 118:257–260PubMedCrossRefPubMedCentralGoogle Scholar
  66. Kaster MP, Machado NJ, Silva HB et al (2015) Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. PNAS 112:7833–7838PubMedCrossRefPubMedCentralGoogle Scholar
  67. Kerkhofs A, Xavier AC, Silva BS et al (2018) Caffeine controls glutamatergic synaptic transmission and pyramidal neuron excitability in human neocortex. Front Pharmacol 8:899PubMedPubMedCentralCrossRefGoogle Scholar
  68. Koffie RM, Meyer-Luehmann M, Hashimoto T et al (2009) Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. PNAS 106:4012–4017PubMedCrossRefPubMedCentralGoogle Scholar
  69. Laurent C, Eddarkaoui S, Derisbourg M et al (2014) Beneficial effects of caffeine in a transgenic model of Alzheimer’s disease-like tau pathology. Neurobiol Aging 35:2079–2090PubMedCrossRefPubMedCentralGoogle Scholar
  70. Laurent C, Burnouf S, Ferry B et al (2016) A2A adenosine receptor deletion is protective in a mouse model of Tauopathy. Mol Psychiatry 21:97–107PubMedCrossRefPubMedCentralGoogle Scholar
  71. Leite MR, Wilhelm EA, Jesse CR et al (2011) Protective effect of caffeine and a selective A2A receptor antagonist on impairment of memory and oxidative stress of aged rats. Exp Gerontol 46:309–315PubMedCrossRefPubMedCentralGoogle Scholar
  72. Lemos C, Pinheiro BS, Beleza RO et al (2015) Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain. Purinergic Signal 11:561–569PubMedPubMedCentralCrossRefGoogle Scholar
  73. Lesné SE, Sherman MA, Grant M et al (2013) Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136:1383–1398PubMedPubMedCentralCrossRefGoogle Scholar
  74. Li P, Rial D, Canas PM et al (2015a) Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. Mol Psychiatry 20:1481PubMedCrossRefPubMedCentralGoogle Scholar
  75. Li S, Geiger NH, Soliman ML et al (2015b) Caffeine, through adenosine A3 receptor-mediated actions, suppresses amyloid-beta protein precursor internalization and amyloid-beta generation. J Alzheimers Dis 47:73–83PubMedPubMedCentralCrossRefGoogle Scholar
  76. Liu CC, Liu CC, Kanekiyo T et al (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118PubMedPubMedCentralCrossRefGoogle Scholar
  77. Lopes LV, Cunha RA, Ribeiro JA (1999a) Cross talk between A1 and A2A adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol 82:3196–3203PubMedCrossRefPubMedCentralGoogle Scholar
  78. Lopes LV, Cunha RA, Ribeiro JA (1999b) Increase in the number, G protein coupling, and efficiency of facilitatory adenosine A2A receptors in the limbic cortex, but not striatum, of aged rats. J Neurochem 73:1733–1738PubMedCrossRefPubMedCentralGoogle Scholar
  79. Lu J, Cui J, Li X et al (2016) An anti-Parkinson’s disease drug via targeting adenosine A2A receptor enhances amyloid-beta generation and gamma-secretase activity. PLoS One 11:e0166415PubMedPubMedCentralCrossRefGoogle Scholar
  80. Lupien SJ, Nair NP, Brière S et al (1999) Increased cortisol levels and impaired cognition in human aging: implication for depression and dementia in later life. Rev Neurosci 10:117–139PubMedCrossRefPubMedCentralGoogle Scholar
  81. Machado NJ, Simões AP, Silva HB et al (2017) Caffeine reverts memory but not mood impairment in a depression-prone mouse strain with up-regulated adenosine A2A receptor in hippocampal glutamate synapses. Mol Neurobiol 54:1552–1563PubMedCrossRefPubMedCentralGoogle Scholar
  82. Magistretti PJ, Hof PR, Martin JL (1986) Adenosine stimulates glycogenolysis in mouse cerebral cortex: a possible coupling mechanism between neuronal activity and energy metabolism. J Neurosci 6:2558–2562PubMedCrossRefPubMedCentralGoogle Scholar
  83. Maia L, de Mendonça A (2002) Does caffeine intake protect from Alzheimer’s disease? Eur J Neurol 9:377–382PubMedCrossRefPubMedCentralGoogle Scholar
  84. Mastroeni D, McKee A, Grover A et al (2009) Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One 4:e6617PubMedPubMedCentralCrossRefGoogle Scholar
  85. Matos M, Augusto E, Machado NJ et al (2012) Astrocytic adenosine A2A receptors control the amyloid-β peptide-induced decrease of glutamate uptake. J Alzheimers Dis 31:555–567PubMedCrossRefPubMedCentralGoogle Scholar
  86. Meerlo P, Roman V, Farkas E et al (2004) Ageing-related decline in adenosine A1 receptor binding in the rat brain: an autoradiographic study. J Neurosci Res 78:742–748PubMedCrossRefPubMedCentralGoogle Scholar
  87. Mitchell RM, Neafsey EJ, Collins MA (2009) Essential involvement of the NMDA receptor in ethanol preconditioning-dependent neuroprotection from amyloid-beta in vitro. J Neurochem 111:580–588PubMedPubMedCentralCrossRefGoogle Scholar
  88. Montine TJ, Koroshetz WJ, Babcock D et al (2014) Recommendations of the Alzheimer’s disease-related dementias conference. Neurology 83:851–860PubMedPubMedCentralCrossRefGoogle Scholar
  89. Moreira A, Diógenes MJ, de Mendonça A et al (2016) Chocolate consumption is associated with a lower risk of cognitive decline. J Alzheimers Dis 53:85–93PubMedCrossRefPubMedCentralGoogle Scholar
  90. Mormino EC, Brandel MG, Madison CM et al (2012) Aβ deposition in aging is associated with increases in brain activation during successful memory encoding. Cereb Cortex 22:1813–1823PubMedCrossRefPubMedCentralGoogle Scholar
  91. Müller UC, Deller T, Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18:281–298PubMedCrossRefPubMedCentralGoogle Scholar
  92. Musiek ES, Holtzman DM (2015) Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat Neurosci 18:800–806PubMedPubMedCentralCrossRefGoogle Scholar
  93. Muthaiyah B, Essa MM, Lee M et al (2014) Dietary supplementation of walnuts improves memory deficits and learning skills in transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 42:1397–1405PubMedCrossRefPubMedCentralGoogle Scholar
  94. Nagpure BV, Bian JS (2014) Hydrogen sulfide inhibits A2A adenosine receptor agonist induced beta-amyloid production in SH-SY5Y neuroblastoma cells via a cAMP dependent pathway. PLoS One 9:e88508PubMedPubMedCentralCrossRefGoogle Scholar
  95. Nehlig A (2018) Interindividual differences in caffeine metabolism and their potential impact on caffeine consumption and biological effects. Pharmacol Rev 70:384–411Google Scholar
  96. Nehlig A, Daval JL, Debry G (1992) Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Rev 17:139–170PubMedCrossRefPubMedCentralGoogle Scholar
  97. Ngandu T, Lehtisalo J, Solomon A et al (2015) A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomized controlled trial. Lancet 385:2255–2263PubMedCrossRefPubMedCentralGoogle Scholar
  98. Orr AG, Hsiao EC, Wang MM et al (2015) Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci 18:423–434PubMedPubMedCentralCrossRefGoogle Scholar
  99. Orr AG, Lo I, Schumacher H et al (2017) Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis 110:29–36PubMedCrossRefPubMedCentralGoogle Scholar
  100. Pagnussat N, Almeida AS, Marques DM et al (2015) Adenosine A2A receptors are necessary and sufficient to trigger memory impairment in adult mice. Br J Pharmacol 172:3831–3845PubMedPubMedCentralCrossRefGoogle Scholar
  101. Pagonopoulou O, Angelatou F (1992) Reduction of A1 adenosine receptors in cortex, hippocampus and cerebellum in ageing mouse brain. Neuroreport 3:735–737PubMedCrossRefGoogle Scholar
  102. Panza F, Solfrizzi V, Barulli MR et al (2015) Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review. J Nutr Health Aging 19:313–328PubMedCrossRefGoogle Scholar
  103. Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431PubMedCrossRefGoogle Scholar
  104. Petersen RC, Roberts RO, Knopman DS et al (2009) Mild cognitive impairment: ten years later. Arch Neurol 66:1447–1455PubMedPubMedCentralCrossRefGoogle Scholar
  105. Pliássova A, Lopes JP, Lemos C et al (2016a) The association of amyloid-β protein precursor with α- and β-secretases in mouse cerebral cortex synapses is altered in early Alzheimer’s disease. Mol Neurobiol 53:5710–5721PubMedCrossRefPubMedCentralGoogle Scholar
  106. Pliássova A, Canas PM, Xavier AC et al (2016b) Age-related changes in the synaptic density of amyloid-β protein precursor and secretases in the human cerebral cortex. J Alzheimers Dis 52:1209–1214PubMedCrossRefPubMedCentralGoogle Scholar
  107. Popp J, Wolfsgruber S, Heuser I et al (2015) Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer’s type. Neurobiol Aging 36:601–607PubMedCrossRefPubMedCentralGoogle Scholar
  108. Prasanthi JR, Dasari B, Marwarha G et al (2010) Caffeine protects against oxidative stress and Alzheimer’s disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radic Biol Med 49:1212–1220PubMedPubMedCentralCrossRefGoogle Scholar
  109. Prediger RD, Batista LC, Takahashi RN (2005) Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiol Aging 26:957–964PubMedCrossRefPubMedCentralGoogle Scholar
  110. Prince M, Comas-Herrera A, Knapp M et al (2016) World Alzheimer report. Alzheimer’s Disease International.
  111. Raichle ME, MacLeod AM, Snyder AZ et al (2001) A default mode of brain function. PNAS 98:676–682PubMedCrossRefPubMedCentralGoogle Scholar
  112. Rajaram S, Valls-Pedret C, Cofán M et al (2017) The walnuts and healthy aging study (WAHA): protocol for a nutritional intervention trial with walnuts on brain aging. Front Aging Neurosci 8:333PubMedPubMedCentralCrossRefGoogle Scholar
  113. Rebola N, Sebastião AM, de Mendonça A et al (2003) Enhanced adenosine A2A receptor facilitation of synaptic transmission in the hippocampus of aged rats. J Neurophysiol 90:1295–1303PubMedCrossRefGoogle Scholar
  114. Rebola N, Canas PM, Oliveira CR et al (2005) Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat. Neuroscience 132:893–903PubMedCrossRefGoogle Scholar
  115. Rebola N, Simões AP, Canas PM et al (2011) Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. J Neurochem 117:100–111PubMedCrossRefPubMedCentralGoogle Scholar
  116. Rial D, Lemos C, Pinheiro H et al (2016) Depression as a glial-based synaptic dysfunction. Front Cell Neurosci 9:521PubMedPubMedCentralCrossRefGoogle Scholar
  117. Rodrigues RJ, Canas PM, Lopes LV et al (2008) Modification of adenosine modulation of acetylcholine release in the hippocampus of aged rats. Neurobiol Aging 29:1597–1601PubMedCrossRefPubMedCentralGoogle Scholar
  118. Santos C, Costa J, Santos J et al (2010) Caffeine intake and dementia: systematic review and meta-analysis. J Alzheimers Dis 20(Suppl 1):S187–S204PubMedCrossRefPubMedCentralGoogle Scholar
  119. Scheff SW, Price DA, Schmitt FA et al (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–1508PubMedCrossRefGoogle Scholar
  120. Sebastião AM, Cunha RA, de Mendonça A et al (2000) Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats. Br J Pharmacol 131:1629–1634PubMedPubMedCentralCrossRefGoogle Scholar
  121. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791PubMedCrossRefPubMedCentralGoogle Scholar
  122. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608PubMedPubMedCentralCrossRefGoogle Scholar
  123. Selkoe D, Mandelkow E, Holtzman D (2012) Deciphering Alzheimer disease. Cold Spring Harb Perspect Med 2:a011460PubMedPubMedCentralCrossRefGoogle Scholar
  124. Serrano-Pozo A, Frosch MP, Masliah E et al (2011) Neuropathological alterations in Alzheimer’s disease. Cold Spring Harb Perspect Med 1:a006189PubMedPubMedCentralCrossRefGoogle Scholar
  125. Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842PubMedPubMedCentralCrossRefGoogle Scholar
  126. Simonin C, Duru C, Salleron J et al (2013) Association between caffeine intake and age at onset in Huntington’s disease. Neurobiol Dis 58:179–182PubMedCrossRefPubMedCentralGoogle Scholar
  127. Solfrizzi V, Frisardi V, Seripa D et al (2011) Mediterranean diet in predementia and dementia syndromes. Curr Alzheimer Res 8:520–542PubMedCrossRefPubMedCentralGoogle Scholar
  128. Solomon A, Kivipelto M, Soininen H (2013) Prevention of Alzheimer’s disease: moving backward through the lifespan. J Alzheimers Dis 1:S465–S469Google Scholar
  129. Sperlágh B, Zsilla G, Baranyi M et al (1997) Age-dependent changes of presynaptic neuromodulation via A1 adenosine receptors in rat hippocampal slices. Int J Dev Neurosci 15:739–747PubMedCrossRefPubMedCentralGoogle Scholar
  130. Sperling RA, Dickerson BC, Pihlajamaki M et al (2010) Functional alterations in memory networks in early Alzheimer’s disease. NeuroMolecular Med 12:27–43PubMedPubMedCentralCrossRefGoogle Scholar
  131. Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292PubMedPubMedCentralCrossRefGoogle Scholar
  132. Tanzi RE (2013) A brief history of Alzheimer’s disease gene discovery. J Alzheimers Dis 33(Suppl 1):S5–S13PubMedPubMedCentralGoogle Scholar
  133. Tariq S, Barber PA (2017) Dementia risk and prevention by targeting modifiable vascular risk factors. J Neurochem 144:565Google Scholar
  134. Tentolouris-Piperas V, Ryan NS, Thomas DL et al (2017) Brain imaging evidence of early involvement of subcortical regions in familial and sporadic Alzheimer’s disease. Brain Res 1655:23–32PubMedCrossRefPubMedCentralGoogle Scholar
  135. Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRefGoogle Scholar
  136. Tomiyama T, Nagata T, Shimada H et al (2008) A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann Neurol 63:377–387PubMedCrossRefGoogle Scholar
  137. Travassos M, Santana I, Baldeiras I et al (2015) Does caffeine consumption modify cerebrospinal fluid amyloid-β levels in patients with Alzheimer’s disease? J Alzheimers Dis 47:1069–1078PubMedCrossRefGoogle Scholar
  138. Ułas J, Brunner LC, Nguyen L et al (1993) Reduced density of adenosine A1 receptors and preserved coupling of adenosine A1 receptors to G proteins in Alzheimer hippocampus: a quantitative autoradiographic study. Neuroscience 5:843–854CrossRefGoogle Scholar
  139. van Gelder BM, Buijsse B, Tijhuis M et al (2007) Coffee consumption is inversely associated with cognitive decline in elderly European men: the FINE study. Eur J Clin Nutr 61:226–232PubMedCrossRefPubMedCentralGoogle Scholar
  140. Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252PubMedPubMedCentralCrossRefGoogle Scholar
  141. Viana da Silva S, Haberl MG, Zhang P et al (2016) Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors. Nat Commun 7:11915PubMedPubMedCentralCrossRefGoogle Scholar
  142. Vollert C, Forkuo GS, Bond RA et al (2013) Chronic treatment with DCPCX, an adenosine A1 antagonist, worsens long-term memory. Neurosci Lett 548:296–300PubMedPubMedCentralCrossRefGoogle Scholar
  143. Weiner MW, Veitch DP, Aisen PS et al (2015) 2014 update of the Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement 11:e1–e120PubMedPubMedCentralCrossRefGoogle Scholar
  144. Yu NY, Bieder A, Raman A et al (2017) Acute doses of caffeine shift nervous system cell expression profiles toward promotion of neuronal projection growth. Sci Rep 7:11458PubMedPubMedCentralCrossRefGoogle Scholar
  145. Zeitlin R, Patel S, Burgess S et al (2011) Caffeine induces beneficial changes in PKA signaling and JNK and ERK activities in the striatum and cortex of Alzheimer’s transgenic mice. Brain Res 1417:127–136PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Paula M. Canas
    • 1
  • Rodrigo A. Cunha
    • 1
    • 2
  • Paula Agostinho
    • 1
    • 2
    Email author
  1. 1.CNC-Center for Neuroscience and Cell Biology, University of CoimbraCoimbraPortugal
  2. 2.FMUC-Faculty of Medicine, University of CoimbraCoimbraPortugal

Personalised recommendations