Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer’s Disease

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson’s and Huntington’s diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined. Objective: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors. Methods: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls. Results: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p < 0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p < 0.01). Conclusion: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia.

A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer’s Disease

“…Specifically, an increase in A 2A expression has been found in hippocampal neurons of aged or AD animal models as well as in astrocytes of AD patients and aged mice [62,[64][65][66][67][68][69]. Interestingly, an increased hippocampal density of A 2A receptors has also been observed in AD patients [61,70,71] (Table 3). [71] Abbreviations: swedish mutation (Sw) transgenic (Tg), Indiana (Ind) mutations.…”

“…Specifically, an increase in A2A expression has been found in hippocampal neurons of aged or AD animal models as well as in astrocytes of AD patients and aged mice [62,[64][65][66][67][68][69]. Interestingly, an increased hippocampal density of A2A receptors has also been observed in AD patients [61,70,71] (Table 3). While A 2A receptor hippocampal expression is generally protective, facilitating BDNF modulation of hippocampal synaptic transmission, in aging its overexpression takes place triggering deleterious synaptic effect causing an LTP-to-LTD shift and a reduction of hippocampal-dependent learning and memory processes.…”

Adenosine and Inflammation: Here, There and Everywhere

“…The modulation of neuroinflammation by ARs makes them an attractive pharmacological target for neurodegenerative diseases that share chronic brain inflammation as a ubiquitous common feature, including Alzheimer’s disease [ 176 , 177 ], Parkinson’s disease [ 178 , 179 ], multiple sclerosis [ 180 , 181 ], and Huntington’s disease [ 182 ]. Remarkably, an alteration of A 2A ARs was found in the brain and peripheral blood cells of patients affected by such neurodegenerative diseases [ 183 , 184 , 185 , 186 , 187 , 188 ].…”

Adenosine A2A Receptors as Biomarkers of Brain Diseases

“…A 2A R are not only located in the brain, but are also present in several peripheral tissues, namely in different blood cells such as leukocytes and platelets (reviewed in Gessi et al, 2000). Based on the association of brain diseases with A 2A R up-regulation in afflicted brain regions, several studies explored if A 2A R in blood cells could be biomarkers of brain diseases, such as AD (Arosio et al, 2010(Arosio et al, , 2016Merighi et al, 2021), PD (Falconi et al, 2019), or ALS (Vincenzi et al, 2013). However, only the understanding of the mechanisms underlying A 2A R up-regulation in brain diseases will allow providing a rationale (or lack of thereof) to consider alterations of the density of peripheral A 2A R as valid readouts of altered A 2A R density that occurs selectively in afflicted brain circuits in the diseased brain.…”