Heme oxygenase-1 derived carbon monoxide suppresses Aβ1–42 toxicity in astrocytes

Abstract

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid β peptides ((Aβ; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Aβ(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, Aβ(1-42) raises peroxynitrite levels in astrocytes, and Aβ(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following Aβ(1-42) application were derived from NADPH oxidase. Induction of haem oxygenase-1 (HO-1) protected astrocytes from Aβ(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by Aβ(1-42). Under hypoxic conditions (0.5% O2, 48 h) HO-1 was induced in astrocytes and Aβ(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that Aβ(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system.

Dexmedetomidine attenuates the toxicity of β‑amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5

“…Aβ causes neuronal cell death in the development of AD, resulting in cognitive and behavioral deficits (28,29). The neuronal cell death is closely related to Aβ-induced oxidative stress and consequent activation of pro-apoptosis signaling, because antioxidative substances and inhibition of apoptosis signaling, alone or in combination, prevent the cell death (30)(31)(32). Astrocytes, a major glial cell type in the brain, participate in the neuropathogenic mechanisms after chronic exposure to Aβ (30).…”

“…The neuronal cell death is closely related to Aβ-induced oxidative stress and consequent activation of pro-apoptosis signaling, because antioxidative substances and inhibition of apoptosis signaling, alone or in combination, prevent the cell death (30)(31)(32). Astrocytes, a major glial cell type in the brain, participate in the neuropathogenic mechanisms after chronic exposure to Aβ (30). Aβ can activate astrocytes and then induce the release of inflammatory and neurotoxic molecules, contributing to chronic neuroinflammation and neuronal death (30).…”

“…Astrocytes, a major glial cell type in the brain, participate in the neuropathogenic mechanisms after chronic exposure to Aβ (30). Aβ can activate astrocytes and then induce the release of inflammatory and neurotoxic molecules, contributing to chronic neuroinflammation and neuronal death (30). It is noteworthy that activated astrocytes have increased levels of the three essential components for Aβ production: amyloid precursor protein, β-secretase and γ-secretase, indicating a vicious circle between Aβ production and astrocyte activation (30).…”

Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells

“…Hmox1, the inducible form of heme oxygenase, degrades heme to three products − ferrous ions, carbon monoxide, and biliverdin. In addition to this catalytic function in heme metabolism, Hmox1 may function as a cytoprotective factor through its end‐products with antioxidant, anti‐inflammatory, anti‐apoptotic, and cell‐signaling properties . Several studies have demonstrated the tissue protective properties of Hmox1 in mouse and rat models of cardiovascular, pulmonary, kidney, gastrointestinal, brain or skin injury, and disease .…”

Regenerative Potential of Carbon Monoxide in Adult Neural Circuits of the Central Nervous System

“…In contrast, transient HO-1 upregulation by CORMs may be beneficial for AD therapies because several in vitro experiments demonstrate cytoprotective effects of CO. Treatment of astrocytes with CORM-2 suppresses the NOX-derived ROS caused by Aβ , which may be mediated by HO-1 induction [171]. CORM-2 can protect neurons from ROS-mediated apoptosis by inhibiting voltage-dependent K + (Kv) channels (i.e., Kv 2.1 ), which facilitates intracellular K + efflux as an initiating step in the apoptotic cascade [172].…”