Alzheimer's disease diagnosis using blood platelets as a circulating mirror of neurons

Abstract:

Alzheimer's disease (AD) is a neurodegenerative pathology covering about 70% of all cases of dementia. Usually the diagnosis of AD is carried out in the dementia phase, often in the moderate stages when treatment efficacy is limited. Indeed, early diagnosis, when possible, is invasive and expensive in routine settings. Circulating platelets have been suggested as an alternate model to study neural dysfunctions and resident neurons and blood platelets both have similar subcellular structures and protein compositions. One of the most surprising findings is that a number of proteins are frequently expressed in both circulating platelets and neurons such as the neuronal protein reelin, which controls cell migration and synaptic plasticity, the amyloid precursor protein (APP), which produces amyloid Aβ peptides that accumulate in senile plaques in AD, brain-derived neurotrophic factor, and the neurotransmitter serotonin, which plays significant roles in regulating behavior and social interaction. Therefore platelets appear as an approachable peripheral biomarker to track the start and course of neurological illnesses. Adenosine, an ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor (A2AAR) is up-regulated in platelets of patients affected by AD and Huntington’s diseases, reflecting the same alteration found in brain tissues. PKCε, closely related with pathological devastation observed in AD, is highly expressed in the healthy brain while downregulated in AD neurons but its peripheral expression in this pathology is not known. It has to be remarked that PKCε activators are now under investigation in Phase II clinical trials in AD patients making PKCε a possible marker of the disease.In this research project we will verify whether the expression of A2AAR/PKCε could be exploited as a specific and sensitive double platelet biomarker for the diagnosis of AD. Finally, the effect of A2AAR and PKCε stimulation on neurotoxicity induced by Aβ-amyloid peptide in neuronal cells will be investigated. Altogether, the recognition of A2AARs/PKCε as a biomarker would improve the early detection of AD and related dementia and may represent the proof of concept to extend the use of A2AAR antagonists as new drugs for AD treatment.