Upregulation of Cortical A_2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer’s Disease

Article type: Research Article

Authors: Merighi, Stefania^a | Battistello, Enrica^a | Casetta, Ilaria^b | Gragnaniello, Daniela^c | Poloni, Tino Emanuele^d | Medici, Valentina^d | Cirrincione, Alice^d | Varani, Katia^a | Vincenzi, Fabrizio^a | Borea, Pier Andrea^a | Gessi, Stefania^{a; *}

Affiliations: [a] Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy | [b] Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy | [c] Department of Neurosciences and Rehabilitation, Ferrara University Hospital, Ferrara, Italy | [d] Department of Neurology & Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, Milan, Italy

Correspondence: [*] Correspondence to: Prof. Stefania Gessi, University of Ferrara, Department of Morphology, Surgery and Experimental Medicine, Pharmacology Unit, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy. Tel.: +39 0532 455497; E-mail: gss@unife.it.

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.

Keywords: A_2A adenosine receptor antagonist, A_2A adenosine receptor overexpression, Alzheimer’s disease, biomarker, drug target, platelets

DOI: 10.3233/JAD-201437

Journal: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1105-1117, 2021