An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer’s Disease Treatment?

Abstract

According to DSM5, the term neurocognitive disorder (NCD) emphasizes that the cause of mental deficit lies in a pathology affecting neuronal circuits. The early clinical stages of NCD (mild-NCD/MCI) are characterized by functional preservation of everyday activities. Instead, if the disorder has a functional impact it is defined as major-NCD (dementia). On the other hand, the definition of the underlying pathology allows for the etiological classification of NCD (American Psychiatric Association, 2013; Sachdev et al., 2015). Based on the pathological deposition of proteins in brain tissue, NCD due to AD is characterized by a dual proteinopathy in which neurodegeneration is associated with the deposition of amyloid and phosphorylated TAU protein (pTAU). AD is the main age-related degenerative NCD progressively involving memory, complex attention, executive functions, language, and visual-perceptual functions. Personality and behavioural changes are also frequent further complicating the clinical course. On the other hand, due to the late involvement of the movement centers, motor function is usually spared until the most advanced stages of the disease. The AD syndromic evolution reflects the progressive spread of pTAU pathology from the allocortex (entorhinal cortex and hippocampus) to the neocortex (Elahi and Miller, 2017; Hanseeuw et al., 2019). Observing the neuropathology of AD is the starting point for deciphering its pathophysiological mechanisms and, therefore, identifying the biomarkers of the disease and the possible therapeutic targets. The macroscopic pathological feature characterizing advanced AD is diffuse brain atrophy due to widespread neurodegeneration causing synaptic and neuronal loss. Actually, the disease begins decades earlier with amyloid accumulation in the neocortex but amyloid deposition, which is very common even in physiological aging, is not sufficient to cause AD. The fundamental question is: what triggers neurodegeneration? Probably, the excess of amyloid-beta (Aβ) induces neurodegeneration through toxic oligomers. Indeed, soluble Aβ oligomers cause a synaptic reduction with a decrease in long-term potentiation and memory. Moreover, oligomers can reduce blood flow in brain capillaries and induce hyperphosphorylation of the AD-relevant epitopes of TAU protein (Selkoe and Hardy 2016; Nortley et al., 2019). Thus, Aβ load triggers neurodegeneration through oligomers which induce unbalanced activation of neuronal kinases resulting in excessive production of pTAU that, in turn, aggregates in pTAU toxic oligomers and spreads from its initial location in allocortex to neocortex. Together, oligomeric Aβ, synaptic pTAU aggregates and glial inflammatory activation are the main neurotoxic factors involved in the manifestation of a clinically relevant neurocognitive disorder (Perez-Nievas et al., 2013; Jack et al., 2018a). Typically, AD pathology shows extracellular accumulation of Aβ peptides (Aβ or senile plaques), as well as the hyperphosphorylated tau protein aggregates inside the dying neurons named neurofibrillary tangles (NFT) and neuropil threads (NT). Their combination constitutes the neuritic plaque (NP), which is the most typical feature of AD neuropathology. Thus, the neuropathological definition of AD requires a combination of scores for Amyloid, TAU (Braak stages), and NP (CERAD), which constitute the ABC criteria for the grading of AD related pathology (Mirra et al., 1991; Braak et al., 2006; Montine et al., 2012). Senile and neuritic plaques, consisting of protein and cellular debris, activate reactive and inflammatory processes by astrocytes and microglia which produce cytokines (IL-1β, IL-6) and NLRP3 inflammosome activation that, in turn, increase neurotoxic phenomena (Serrano-Pozo et al., 2016; Ising et al., 2019). On the basis of the neuropathological picture, several biomarkers have been developed for the in vivo definition of the pathology. Thus, the ATN system (Amyloid-TAU-Neurodegeneration) has been set up including 1) estimate of the amyloid load: Aβ decrease in cerebrospinal fluid (CSF) and/or Aβ cortical accumulation at amyloid-PET; 2) pTAU valuation: pTAU increase in CSF and/or pTAU cortical accumulation at TAU-PET; 3) extent of neurodegeneration: atrophic pattern at brain MRI and/or hypometabolism at FDG-PET and/or increase of total-TAU in CSF (Jack et al., 2018b; Chételat et al., 2020). These markers can allow for early diagnosis or even can identify those most at risk of developing AD in a preclinical phase (before mild-NCD) in order to implement timely therapeutic interventions (Dubois et al., 2016). Nonetheless, there is now no cure for AD and this approach poses ethical problems, as well as being invasive and expensive; therefore, an intensive search for biomarkers obtainable from peripheral blood is still in progress (Lewczuk et al., 2018; Molinuevo et al., 2018). The early mechanisms leading to Aβ accumulation and initial generation of toxic molecules are elusive and multiple, and belong to the individual trajectory of cerebral aging linked to non-modifiable genetic factors (AD-related polymorphisms, APO-E4 allele, and pathogenic mutations in PSN-1-2 and APP genes, and Williamson et al., 2009; Vermunt et al., 2019), and to modifiable factors related to the individual’s personal history including favorable behaviors (regular physical and mental activity, high education, healthy diet, social engagement) and harmful conditions (midlife obesity, diabetes, hypertension, smoke, excessive alcohol, and hearing loss) (Lourida et al., 2019; Livingston et al., 2020). Early pathogenesis of sporadic AD is quite complex. Just as there are different forms of hepatitis that lead to cirrhosis, there are different pathophysiological paths that lead to AD. However, the sine qua non for the development of AD...