A critical role of TRPM2 channel in A[beta]42-induced microglial activation and generation of tumor necrosis factor-[alpha]

• Published in: Glia 2018-03, Vol.66 (3), p.562
• Main Authors: Alawieyah Syed Mortadza, Sharifah, Sim, Joan A, Neubrand, Veronika E, Jiang, Lin-Hua
• Format: Article
• Language: English
• Subjects: Ablation; Activation; Alzheimer's disease; Kinases; Necrosis; Positive feedback; Reactive oxygen species
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23265

Amyloid [beta] (A[beta])-induced neuroinflammation plays an important part in Alzheimer's disease (AD). Emerging evidence supports a role for the transient receptor potential melastatin-related 2 (TRPM2) channel in A[beta]-induced neuroinflammation, but how A[beta] induces TRPM2 channel activation and this relates to neuroinflammation remained poorly understood. We investigated the mechanisms by which A[beta]42 activates the TRPM2 channel in microglial cells and the relationships to microglial activation and generation of tumor necrosis factor-[alpha] (TNF-[alpha]), a key cytokine implicated in AD. Exposure to 10-300 nM A[beta]42 induced concentration-dependent microglial activation and generation of TNF-[alpha] that were ablated by genetically deleting (TRPM2 knockout ;TRPM2-KO) or pharmacologically inhibiting the TRPM2 channel, revealing a critical role of this channel in A[beta]42-induced microglial activation and generation of TNF-[alpha]. Mechanistically, A[beta]42 activated the TRPM2 channel via stimulating generation of reactive oxygen species (ROS) and activation of poly(ADPR) polymerase-1 (PARP-1). A[beta]42-induced generation of ROS and activation of PARP-1 and TRPM2 channel were suppressed by inhibiting protein kinase C (PKC) and NADPH oxidases (NOX). A[beta]42-induced activation of PARP-1 and TRPM2 channel was also reduced by inhibiting PYK2 and MEK/ERK. A[beta]42-induced activation of PARP-1 was attenuated by TRPM2-KO and moreover, the remaining PARP-1 activity was eliminated by inhibiting PKC and NOX, but not PYK2 and MEK/ERK. Collectively, our results suggest that PKC/NOX-mediated generation of ROS and subsequent activation of PARP-1 play a role in A[beta]42-induced TRPM2 channel activation and TRPM2-dependent activation of the PYK2/MEK/ERK signalling pathway acts as a positive feedback to further facilitate activation of PARP-1 and TRPM2 channel. These findings provide novel insights into the mechanisms underlying A[beta]-induced AD-related neuroinflammation.