IL RECETTORE ADENOSINICO A2A COME POSSIBILE BIOMARCATORE NELLA DIAGNOSI DIFFERENZIALE DELLE DEMENZE NELL'ANZIANO.

Although Alzheimer’s disease (AD) might be best designated as a purely degenerative disease in whose pathogenesis amyloid-beta plays a key role, it is acknowledged that in elder patients (>65years) there is an increased likelihood of other neuropathological abnormalities including cerebrovascular lesions. Over the last years, there has been accumulating evidence that the previously held sharp distinction between AD and vascular dementia (VaD) may not be so clear-cut, especially in old age. VaD is the second most common cause of dementia after AD. VaD arises as a consequence of ischemic insults such as hemorrhage and hypoperfusion that trigger neurodegeneration by depriving nerve cells of oxygen and glucose. Such deprivation results in the depletion of nerve cell energy supplies, leading to membrane depolarization, followed by an excessive release of glutamate which activates the N-methyl-D-aspartate receptor (NMDAR). This allows the influx of toxic levels of Ca2+ into nerve cells, which, in turn, activates intracellular calcium-dependent enzymes. The purine ribonucleoside adenosine (Ado) is a naturally occurring metabolite that is ubiquitously distributed throughout the body as a metabolic intermediary. Intra- and extracellular Ado levels rise in response to physiological stimuli and with metabolic/energetic perturbations, inflammatory challenges and tissue injury. The physiological responses to Ado take place as a result of the binding and activation of different transmembrane receptors: the high-affinity A1 and A2A (A2AR) receptors, the low-affinity A2B receptor, or the low-abundance A3 receptor. It has been demonstrated that A2AR is able to prevent amyloid--induced synaptotoxicity in animal models and cell cultures. Moreover A2AR has been shown to control NMDA currents and glutamate outflow in the hippocampus. Contrasting data have been reported so far on the beneficial/detrimental effects of A2AR on brain cells. The blockade of A2AR alleviates the long-term burden of brain disorders such as ischemia, epilepsy, Parkinson’s or Alzheimer’s disease. On the other hand, agonists of A2AR can protect the Central Nervous System against several insults, including ischemia and exicitotoxins. In the periphery A2AR contributes to coronary endothelial dilatation in mice, can inhibit endothelial apoptosis and preserves vascular reactivity following hemorrhagic shock in rats. Finally, increasing evidence supports the notion that A2AR is implicated in the downregulation of inflammation. In this study we evaluated the gene and protein expression of A2AR in the peripheral blood mononuclear cells (PBMCs) of patients with VaD, AD, Mild Cognitive Impairment (MCI) and healthy controls in order to investigate its potential role as an easily accessible biomarker in the differential diagnosis of dementia. This study show that A2AR expression is upregulated in the peripheral cells of a-MCI but not AD subjects, supporting an involvement of the Ado system in the early stages of AD. It also shows that A2AR expression is lower in the PBMCs of subjects with VaD than AD, highlighting its possible relevance as a biomarker that may help differentiate two forms of dementia that are often closely associated. From our results it can be concluded that A2AR may play an important but differential role in both types of dementia: its upregulation in the preclinical stages of AD could counterbalance the existing inflammatory state and its downregulation in VaD could reflect the effects of A2AR on the brain vasculature. It can therefore be suggested that A2AR could serve as a biomarker in the differential diagnosis between VaD and AD.