Identification of glia phenotype modulators based on select glial function regulatory signaling pathways

ABSTRACT

Introduction: Despite the considerable social and economic burden on the healthcare system worldwide due to neurodegenerative diseases, there are currently few disease-altering treatment options for many of these conditions. Therefore, new approaches for both prevention and intervention for neurodegenerative diseases are urgently required. Microglia-mediated neurotoxicity is one of the pathologic hallmarks common to Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Current therapeutic approaches to target microglia-mediated neurotoxicity are focused on the identification of glia phenotype modulators (GPMs), which can inhibit the ‘classical’ pro-inflammatory and neurotoxic phenotypes of microglia.

Areas covered: This article reviews selected microglial molecular targets and pathways involved in either neurotoxicity or neuroprotection and how their identification.

Expert opinion: Microglial activation and their signaling pathways have important implications in the neurotoxicity and brain disorders. Pharmacological modulation of microglial activation may serve as a potential therapeutic approach for targeting microglia-mediated neurotoxicity. However, given that microglia change their activation states depending on the timing, stage, and severity of disease, and even aging, the appropriate window should be considered for this approach to be clinically effective. In the future, the identification of unknown extracellular signals and intracellular molecular switches that control phenotypic shifts may facilitate the development of novel therapeutics targeting microglia-mediated neurotoxicity.

KEYWORDS:

• Microglia
• neuroinflammation
• neurotoxicity
• neurodegenerative disease
• drug development

Article highlights

• Microglia-mediated neurotoxicity is a pathologic hallmark in many neurodegenerative diseases.

• Identification of GPMs, which can inhibit the ‘classical’ pro-inflammatory activation of microglia while augmenting the ‘alternative’ anti-inflammatory and neuroprotective phenotypes, is highly desirable.

• Selected microglial molecular targets and pathways of GPMs discussed in this review include oxidative stress, excitoneurotoxicity, P2X7R, HMGB1, GSK-3β, PRX, NRF2, AMPK, PPAR-γ, and JMDJ3.

• The identification of GPMs may serve as a promising approach for the development of disease-modifying treatments for many neurodegenerative diseases.

• Further identification of extracellular signals and intracellular molecular switches that control microglial phenotypes may facilitate the development of novel GPMs targeting microglia-mediated neurotoxicity.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are supported by the National Research Foundation of Korea (NRF) via the Korean government (MSIP) [2015R1A2A1A10051958, 2016M3C7A1904148, NRF-2017R1A5A2015391].