Astrocytes and Adenosine A2 A Receptors: Active Players in Alzheimer's Disease

Abstract

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic "neurocentric" view of Alzheimer's disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A₁R and A_2A R subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A_2A R, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A_2A R levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A_2A R in astrocytes function might shed light on novel therapeutic strategies for AD.

Keywords: Alzheimer’s disease; adenosine A2A receptors; amyloid-β protein; astrocyte reactivity; cognitive deficits; synaptic plasticity.

FIGURE 1

Astrocytes and A_2AR are active players in Alzheimer’s disease (AD). Adenosine A_2A receptors (A_2AR) are upregulated in AD brain, namely in astrocytes. These glial cells are considered the third active element of the synapse, regulating synaptic plasticity, mainly long-term potentiation (LTP) and long-term depression (LTD) that are events mediated by AMPAR and NMDAR (receptors for glutamate). Astrocytes became reactive and dysfunctional in response to amyloid-β peptide (Aβ) overproduction, derived from amyloid-β precursor protein (AβPP) proteolytic cleavage. Astrocyte dysfunction negatively impacts on synaptic plasticity, the neurophysiological basis of memory. A_2AR regulate key functions of astrocytes, such as intracellular Ca²⁺ levels [Ca²⁺]_i, glutamate uptake by the transporter (GLT-1) and the release of ATP, and consequently regulate synaptic plasticity. Thus, A_2AR in astrocytes might be a therapeutical target to manage AD.