Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Abstract

Alzheimer's disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, namely P1 receptors. One of them, the A_2A subtype, is particularly expressed in the brain at the striatal and hippocampal levels and appears as the most promising target to counteract neurological damage and adenosine-dependent neuroinflammation. Extracellular nucleotides (ATP, ADP, UTP, UDP, etc.) are also released from the cell or are synthesized extracellularly. They activate P2X and P2Y membrane receptors, eliciting a variety of physiological but also pathological responses. Among the latter, the chronic inflammation underlying AD is mainly caused by the P2X7 receptor subtype. In this review we offer an overview of the scientific evidence linking P1 and P2 mediated purinergic signaling to AD development. We will also discuss potential strategies to exploit this knowledge for drug development.

Keywords: Alzheimer’s disease; P1 receptors; P2 receptors; neuroinflammation.

Figure 1

Membrane machinery for nucleotide and nucleoside signaling. (1) ATP can be released by the cells in different ways, among which are membrane stress/damage, and molecular (Panx1, Connexin, P2X7) and vesicular transport. Once on the extracellular side of the membrane, ATP either follows a degradative pathway (2) or stimulates P2 receptors (3). In the first case, ATP, through the activity of the CD39 and CD73 enzymes, is transformed into adenosine (ADO), activating P1 (A₁, A_2A, A_2B, and A₃) receptors. ADO can also be transported into the cell by ENT1 and ENT2 proteins or be inactivated to inosine (Ino) by CD26.