Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation

ABSTRACT

Introduction: The importance of microglia in most neurodegenerative pathologies, from Parkinson’s disease to amyotrophic lateral sclerosis and Alzheimer’s disease, is increasingly recognized. Until few years ago, microglial activation in pathological conditions was considered dangerous to neurons due to its causing inflammation. Today we know that these glial cells also play a crucial physiological and neuroprotective role, which is altered in neurodegenerative conditions.

Areas covered: The neuroinflammatory hypothesis for neurodegenerative diseases has led to the trial of anti-inflammatory agents as therapeutics with largely disappointing results. New information about the physiopathological role of microglia has highlighted the importance of immunomodulation as a potential new therapeutic approach. This review summarizes knowledge on microglia as a potential therapeutic target in the most common neurodegenerative diseases, with focus on compounds directed toward the modulation of microglial immune response through specific molecular pathways.

Expert opinion: Here we support the innovative concept of targeting microglial cells by modulating their activity, rather than simply trying to counteract their inflammatory neurotoxicity, as a potential therapeutic approach for neurodegenerative diseases. The advantage of this therapeutic approach could be to reduce neuroinflammation and toxicity, while at the same time strengthening intrinsic neuroprotective properties of microglia and promoting neuroregeneration.

KEYWORDS:

• Drug targets
• immunomodulation
• M2 and M1 phenotypes
• microglia
• neurodegenerative diseases

Article highlights.

• Microglia are the immune cells of the brain that play several roles in both physiological and pathological conditions.

• Neurodegenerative diseases are characterized by microglial activation and neuroinflammation.

• Activated microglia can assume two phenotypes: the pro-inflammatory, ‘classically activated’ M1 phenotype, which contributes to neuroinflammation, and the ‘alternatively activated’ M2 phenotype, which is neuroprotective.

• Anti-inflammatory treatments aiming to counteract or prevent neuroinflammation by blocking microglial activation have been tested as a possible therapeutic option against neurodegenerative diseases, but it failed in most cases.

• Immunomodulation to shift microglial phenotype from the neuroinflammatory M1 to the neuroprotective M2 is a new promising therapeutic approach to counteract neurodegeneration.

• Microglial HMGB1, AMPK, GSK3β, HDACs and PPARγ have been identified as interesting potential cellular and molecular targets for immunomodulation toward neuroprotection.

• Several molecules acting on these targets have been identified as possible immunomodulatory and neuroprotective drugs, but studies are still ongoing.

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Declaration of interest

The authors are supported by the University of Bologna, which fully funded this work. The University of Bologna had no role in the writing of this paper or in the submitting decision. The authors have no other 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 apart from those disclosed.