ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels

Abstract

The most common acute brain insult is ischemic stroke, where transient or permanent reduction in cerebral blood flow deprives the tissue of oxygen and glucose and permits build-up of potentially toxic substances, effects that together lead to rapid or delayed cell death (Dirnagl et al. 1999). An association between Alzheimer's disease (AD) and ischemic stroke has been established. Indeed, patients that on autopsy show cerebral infarcts and AD pathology are more cognitively impaired than patients with AD pathology alone (Snowdon et al. 1997 Abstract Inflammation contributes to neurodegeneration in post-ischemic brain, diabetes, and Alzheimer's disease. Participants in this inflammatory response include activation of microglia and astrocytes. We studied the role of microglia treated with amyloid-b peptide (Ab) on hemichannel activity of astrocytes subjected to hypoxia in high glucose. Reoxygenation after 3 h hypoxia in high glucose induced transient astroglial permeabilization via Cx43 hemichannels and reduction in intercellular communication via Cx43 cell-cell channels. Both responses were greater and longer lasting in astrocytes previously exposed for 24 h to conditioned medium from Ab-treated microglia (CM-Ab). The effects of CM-Ab were mimicked by TNF-a and IL-1b and were abrogated by neutralizing TNF-a with soluble receptor and IL-1b with a receptor antagonist. Astrocytes under basal conditions protected neurons against hypoxia, but exposure to CM-Ab made them toxic to neurons subjected to a sub-lethal hypoxia/reoxygenation episode, revealing the additive nature of the insults. Astrocytes exposed to CM-Ab induced permeabilization of cortical neurons through activation of neuronal pannexin 1 (Panx1) hemichannels by ATP and glutamate released through astroglial Cx43 hemichannels. In agreement, inhibition of NMDA or P2X receptors only partially reduced the activation of neuronal Panx1 hemichannels and neuronal mortality, but simultaneous inhibition of both receptors completely prevented the neurotoxic response. Therefore, we suggest that responses to ATP and glutamate converge in activation of neuronal Panx1 hemichannels. Thus, we propose that blocking hemichannels expressed by astrocytes and/or neurons in the inflamed nervous system could represent a novel and alternative strategy to reduce neuronal loss in various pathological states including Alzheimer's disease, diabetes and ischemia.

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

“…Inflammatory cells, including microglia and astrocytes, are thought to contribute to damage in AD, in part via glutamate excitotoxicity (2,12). For example, exposure to oligomeric Aβ or conditioned medium from microglial cultures incubated with Aβ has been reported to decrease glutamate reuptake from astrocytes in brain slices and cultures (13)(14)(15)(16), but whether Aβ also induces local release of toxic glutamate levels onto neurons remains unknown. To study this question, we used a FRET-based…”

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

“…Activated HCs have been involved in the release of gliotransmitters such as ATP and glutamate as well as chemokines that have deleterious consequences on neurons as reported in murine models of AD [18][19][20], experimental allergic encephalomyelitis [21], amyotrophic lateral sclerosis [20,22] and neuropathic pain [23,24]. In our study, it has also been demonstrated that activated HCs can allow Ca 2+ influx, contributing to a maintenance of high [Ca 2+ ]i.…”

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

“…In mammalian systems purinergic signaling is a crucial component of numerous (patho)physiological phenomena, including synaptic transmission, 12 regulation of vascular tone, 13 inner ear function and hearing, 14 cell volume regulation, 15 ischemic responses in the heart 16 and brain, 17 propagation of intercellular calcium waves, 18,19 the spread of apoptotic cell death, 20 kidney function, 21 hypoxic preconditioning, 22 Alzheimer's Disease, 23 cell proliferation, 24 memory, 25 cancer, 26 embryonic development, 27 nociception, 28 and inflammatory diseases. 29 In addition to these many roles for ATP, recent data indicate a crucial role for extracellular ATP in inflammatory cell targeting to sites of injury.…”