Exploring the Role of P2X Receptors in Alzheimer’s Disease

Abstract

Several studies have pointed to soluble oligomers of beta amyloid peptide (SOAβ) as the principal neurotoxic agents responsible for the generation of synaptotoxic events that can explain the main symptoms of Alzheimer’s disease (AD). Among the toxic features associated with SOAβ, one of the most notorious is the formation of a non-selective pore-like structure in the plasma membrane, which may partly explain the overload of intracellular Ca2+. There is evidence that the pore causes leakage of key intracellular compounds, such as adenosine triphosphate (ATP), to the extracellular milieu. Extracellular ATP activates P2X receptors (P2XR), which are ligand-gated ion channels (LGICs) widely expressed in both neuron and glial cells and act as neuromodulators of synaptic activity by promoting Ca2+ entry and facilitating neurotransmitter release. There is abundant evidence correlating the overexpression of these receptors to neurodegenerative diseases, including AD, thus opening the possibility that P2XR could potentiate the toxic mechanisms induced by SOAβ and contribute to intracellular Ca2+ overload in neurons and other mechanisms related to glial activation and inflammation. In this review, we correlate scientific evidence related to the main toxic effects induced by SOAβ and those that are mediated by purinergic P2XR. The data suggest that these purinergic receptors participate in the deleterious cellular and molecular effects of SOAβ that lead to the pathogenesis of AD. This information sheds light on the participation of new components in SOAβ toxicity that could be interesting as pharmacological targets for the development of molecular or chemical compounds able to modulate them.

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

“…Aβ and the ATP-sensitive ionotropic P2X7R are suggested to play an important role in the pathogenesis of Alzheimer’s disease, a neurodegenerative disorder characterized by a sustained inflammatory response [ 28 ]. To investigate if Aβ 1-42 directly changes the ionotropic function of the human P2X7R, we first performed electrophysiological whole-cell patch-clamp measurements on HEK-P2X7R cells ( Figure 4 ).…”

“…Moreover, this result favors the hypothesis that Aβ 1-42 interacts with monocytic nAChRs. However, some studies pointed out an important role of the P2X7R in Aβ signaling [ 28 , 58 ]. These controversial results might be due to the different experimental protocols and cells used here (monocytic cells) and in the previous studies (microglia).…”

“…APP is an evolutionary highly conserved cell surface protein that is expressed by tissues of all germ layers such as the nervous system, skin, adipose tissue, skeletal muscle, heart, kidney, spleen, gastrointestinal tract, thymus, lung, and liver [ 20 , 21 , 22 , 23 , 24 ]. APP and its cleavage products, including the Aβ peptides, are mainly known for their putative roles in Alzheimer’s disease (AD), the most common dementia and primary neurodegenerative disorder in elderly persons [ 23 , 25 , 26 , 27 , 28 ]. The essential physiological functions of APP that can be predicted because of its evolutionary conservation, however, are incompletely understood.…”

P2X7 Receptor is Involved in Mitochondrial Dysfunction Induced by Extracellular Alpha Synuclein in Neuroblastoma SH-SY5Y Cells

“…Since adenosine 5 -triphosphate (ATP) was proposed as an extracellular signalling molecule with neurotransmitter properties, the function of the purinergic signalling has been thoroughly studied in the central nervous system (CNS). Recent data highlight the involvement of purinergic neurotransmission in the pathogenesis and progression of nervous system disorders including neurodegenerative conditions, such as Alzheimer's (AD) and Parkinson's (PD) diseases [1][2][3]. The contribution of purinergic signalling is complex and involves the combined activity resulting from ATP release, its hydrolysis via ectoenzymes, and receptor activation.…”

“…The contribution of purinergic signalling is complex and involves the combined activity resulting from ATP release, its hydrolysis via ectoenzymes, and receptor activation. Two functional subclasses of membrane-bound P2 purinergic receptors, P2X(1-7) ionotropic receptors, activated by ATP, and G protein-coupled metabotropic P2Y (1)(2)4,6,(11)(12)(13)(14) receptors, activated by ATP, adenosine diphosphate (ADP), and uridine di-and triphosphate (UDP and UTP), mediate the extracellular actions of ATP [4][5][6]. Most studies of the extracellular actions of ATP connected with the short-term neurotransmission and neuromodulation events are related to P2X receptor-mediated Ca 2+ permeability and membrane depolarization.…”