The TRPM2 channel nexus from oxidative damage to Alzheimer’s pathologies: An emerging novel intervention target for age-related dementia

Abstract

Alzheimer's disease (AD), an age-related neurodegenerative condition, is the most common cause of dementia among the elder people, but currently there is no treatment. A number of putative pathogenic events, particularly amyloid β peptide (Aβ) accumulation, are believed to be early triggers that initiate AD. However, thus far targeting Aβ generation/aggregation as the mainstay strategy of drug development has not led to effective AD-modifying therapeutics. Oxidative damage is a conspicuous feature of AD, but this remains poorly defined phenomenon and mechanistically ill understood. The TRPM2 channel has emerged as a potentially ubiquitous molecular mechanism mediating oxidative damage and thus plays a vital role in the pathogenesis and progression of diverse neurodegenerative diseases. This article will review the emerging evidence from recent studies and propose a novel 'hypothesis' that multiple TRPM2-mediated cellular and molecular mechanisms cascade Aβ and/or oxidative damage to AD pathologies. The 'hypothesis' based on these new findings discusses the prospect of considering the TRPM2 channel as a novel therapeutic target for intervening AD and age-related dementia.

An extract of Hypericum perforatum induces wound healing through inhibitions of Ca2+ mobilizations, mitochondrial oxidative stress and cell death in epithelial cells: Involvement of TRPM2 channels

“…3(A)) or presence of HP (Figs. 3(C) and 3(D)), consistent with HP being critical in inhibition of oxidative stress and ADPR-induced TRPM2 channel activation (Nazıroğlu et al, 2013;Özdemir et al, 2016;Uslusoy et al, 2017;Jiang et al, 2018). Similar findings were made regarding the increase of mitochondrial oxidative stress through activation of TRPM2 (Figs.…”

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

“…Amyloid-β peptide-induced ROS generation-mediated activation of the TRPM2 channel results in synaptic loss and neuronal death in hippocampus, 38,41,55 microglial cell activation and generation of proinflammatory mediators 37,55,56 and impairments in the BBB and neurovascular function, 35 supporting a critical role of the TRPM2 channel in the pathogenesis of AD. 57…”

“…There is compelling evidence from recent studies that supports an important role for the TRPM2 channel in mediating microglial cell activation and generation of proinflammatory mediators and neuroinflammation in response to stimulation of oxidative stress or stimuli that known to induce ROS generation such as amyloid-β peptides. 37,56,57 It has been also shown that TRPM2-mediated activation of microglial cells contributes to chronic cerebral hypo-perfusion brain damage 68 and activation of microglia and astrocytes in neonatal hypoxic-ischaemic brain damage. 69 It remains unknown regarding the role of TRPM2dependent microglial activation and neuroinflammation in ischaemia-reperfusion-induced delayed neuronal death.…”

Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signaling

“…It has been proposed that the Piezo1 channel mediates ultrasound‐induced activation of the MEK/ERK signaling pathway in rat DP‐MSCs . The proline‐rich tyrosine kinase 2 (PYK2) is well‐known as a signaling molecule downstream of intracellular Ca 2+ and plays a critical role in mediating Ca 2+ ‐dependent induction of the MEK/ERK pathway in monocyte, microglial, and neuronal cells . There is evidence for involvement of PYK2 in cancer cell migration, but it is unclear whether PYK2 plays a role in the regulation of MSC migration.…”