TRPM2 channel mechanism of neuroinflammation and neurodegeneration in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia and also a major cause of morbidity and mortality. Currently, there is no effective therapeutics to treat or slow the disease progress. The amyloid cascade hypothesis, which continues to be supported by preclinical and clinical studies, holds accumulation of Aβ as the early and initiating factor for AD pathogenesis (Selkoe and Hardy, 2016). Extensive drug discovery efforts targeting Aβ generation however so far have not succeeded in development of AD-modifying drugs, highlighting the need for a better understanding of AD pathogenesis. Microglial cells are immunocompetent cells resident in the brain. Aβ-induced chronic or dysregulated microglial activation and excessive generation of proinflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha), play an important part in Aβ-induced neurotoxicity, and targeting microglia-mediated neuroinflammation has gained increasing interest as a novel approach treating AD (Wes et al., 2016; Colonna and Butovsky 2017; Wolf et al., 2017).

Recent studies from us and others have revealed a key role for the Ca2+-permeable TRPM2 channel in Aβ-induced AD-related neuroinflammation and neurotoxicity (Ostapchenko et al., 2015; Syed Mortadza et al., 2018; Li and Jiang, 2018, Cell Death Dis). The TRPM2 channel is highly expressed in microglial cells and essential for Aβ42-induced microglial activation and generation of TNF-α (Syed Mortadza et al., 2018), a key proinflammatory cytokine strongly implicated in AD pathogenesis. TNF-α is known to act as an autocrine/paracrine signal in inducing microglial activation and neuronal death and thus amplify Aβ-induced neuroinflammation and neurotoxicity. Our preliminary study suggests a role for the TRPM2 channel in both TNF-α induced microglial activation and neurodegeneration. This PhD project aims to investigate the mechanisms by which the TRPM2 channel mediates the dual (microglial and neuronal) signalling roles of TNF-α in Aβ-induced neuroinflammation and neurodegeneration.

Specifically, the project will use multiple techniques that are well established in our lab (Ye et al., 2015; Jiang et al., 2017; Li et al., 2017; Syed Mortadza et al., 2017, 2018; Li and Jiang, 2018), including patch-clamp recording, singe cell imaging, real-time RT-PCR, immunofluorescent microscopy, western blotting, ELISA, and cell death assay, and combine with genetic and pharmacological interventions to address the following:
(1) The signalling mechanisms by which TNF-α activates the TRPM2 channel in microglial cells, leading to microglial activation and generation of proinflammatory mediators (IL-1β, TNF-alpha and ROS) following exposure of wild-type (WT) and TRPM2-knockout (TRPM2-KO) microglial cells to TNF-α;
(2) The signalling mechanisms by which TNF-α activates the TRPM2 channel in hippocampal neurons, resulting in neurotoxicity in WT and TRPM2-KO hippocampal neurons, including synaptic loss, axon degeneration and neuronal death induced by TNF-α;
(3) The role of the TRPM2 channel in mediating contribution of Aβ-induced neuroinflammation by generation of TNF-α, by examining neurotoxicity in WT hippocampal neurons induced by culture media conditioned by WT or TRPM2-KO microglial cells that are prior exposed to Aβ42.

This study is anticipated to provide novel insights into the mechanisms underlying Aβ-induced AD-related neuroinflammation and neurotoxicity.

References:
[1] Selkoe, D.J. and Hardy, J. (2016) EMBO Mol Med 8:595.
[2] Wes, P.D., Sayed, F.A., Bard, F. and Gan, L. (2016) Glia 64:1710.
[3] Colonna, M. and Butovsky, O. (2017) Ann Rev Immunol 35: 441.
[4] Wolf, S.A., … and Kettenmann, H. (2017) Ann Rev Physiol 79:619.
[5] Ostapchenko, V.G., … and Jackson, M.F. (2015) J Neurosci 35: 15157.
[6] Ye, M.,…Luo, J.H. and Jiang, L.-H. (2014) Cell Death Dis 5:e1541.
[7] Syed Mortadza, S., … and Jiang, L.-H. (2017) Sci Rep 7:45032.
[8] Jiang, Q., …, Jiang, L.-H., Yang, W. and Han, F. (2017) Antioxid Redox Signal 27:1297.
[9] Li, X., Yang, W. and Jiang, L.-H. (2017) Front Mol Neurosci 10:414
[10] Syed Mortadza, S.A., … and Jiang, L.-H. (2018) Glia 66:562.
[11] Li, X. and Jiang, L.-H. (2018) Cell Death & Disease 9:195