P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

Abstract

ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na⁺, Ca²⁺, and K⁺, but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca²⁺ influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.

Keywords: Alzheimer’s disease; P2X7 receptor; Parkinson’s disease; amyotrophic lateral sclerosis; epilepsy; ischemia; mechanical injury; multiple sclerosis; neurodegenerative diseases; neuroinflammation; neuropathic pain.

Figure 1

Secretion of interleukin-1β (IL-1β) from microglial cells via involvement of the nucleotide-binding, leucine-rich repeat, pyrin domain containing 3 (NLRP3) inflammasome. Pathogen-associated molecular patterns (PAMPs; e.g., bacterial lipopolysaccharide (LPS)) act on toll-like receptor-4 (TLR4) and cause its phosphorylation. In consequence, in the cell nucleus, NF-κB is activated, which promotes the synthesis of the NLRP3 inflammasome and pro-IL-1β, both accumulating in the cytosol in their inactive forms. The activation of NLRP3 is primarily due to a decrease of the intracellular K⁺ concentration [K⁺]_i, initiated by the stimulation of P2X7Rs by high local concentrations of the molecule ATP, which is considered to be a danger-associated molecular pattern (DAMP). P2X7Rs allow the inward flux of Na⁺/Ca²⁺ and in exchange the outward flux of K⁺, leading to a fall in [K⁺]_i. The opening of two-pore domain potassium channels (2KP) may also lead to an impoverishment of cytoplasmic K⁺. A further stimulus for NLRP3 activation is the outward flux of Cl⁻ through chloride intracellular channels (CLICs). TLR4, P2X7Rs, 2 KP channels, and CLICs are all located in the cell membrane of microglia. A sensor for the fall in [K⁺]_i is the NEC7 serine/threonine kinase. NEC7 is able to form a complex with NLRP3, which is still inactive, but after constitution of a still larger multimeric complex with apoptosis-associated speck-like protein (ASC) binds also pro-caspase-1 (pro-Casp-1). In consequence, pro-Casp-1 is cleaved to Casp-1, which then by its activated form aCasp-1 degrades pro-IL-1β to mature IL-1β. Then, IL-1β leaves the cell by a number of mechanisms to the extracellular space and exerts its effects as a neuroinflammatory cytokine. K⁺ with downward arrow, decrease of the K⁺ concentration. Reproduced with permission from [37].

Figure 2

Effects of activated microglia on neighboring neurons. Soluble β-amyloid (Aβ) aggregates and thereby forms fibrillary plaques surrounded by microglial cells. Microglia are endowed with P2X7Rs, whose stimulation by high concentrations of ATP causes the activation of intracelllular caspase-1 triggering thereby the apoptotic caspase cascade. P2X7R-mediated processes result in the release of inflammatory cytokines (e.g., IL-1β), proteases, reactive oxygen species (ROS) and the excitotoxic glutamate (Glu). During AD, hyperphosphorylated tau forms intracellular neurofibrillary tangles in neurons. All these damaging conditions lead to neuronal necrosis and microglial apoptosis. The binding of IL-1β to its receptors at neurons modifies long-term potentiation (LTP) and -depression (LTD), as well as synaptic transmission. Microglial activation may also cause excessive synaptic pruning by phagocytosis, being a neurodegenerative factor. Reproduced with permission from [145].