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Present and future of microglial pharmacology

  • Author Footnotes
    9 These authors contributed equally to this work
    Eva Šimončičová
    Footnotes
    9 These authors contributed equally to this work
    Affiliations
    Neuroscience Graduate Program, University of Victoria, Victoria, BC, Canada

    Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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  • Author Footnotes
    9 These authors contributed equally to this work
    Elisa Gonçalves de Andrade
    Footnotes
    9 These authors contributed equally to this work
    Affiliations
    Neuroscience Graduate Program, University of Victoria, Victoria, BC, Canada

    Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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  • Haley A. Vecchiarelli
    Affiliations
    Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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  • Ifeoluwa O. Awogbindin
    Affiliations
    Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

    Neuroimmunology Group, Molecular Drug Metabolism and Toxicology Laboratory, Department of Biochemistry, University of Ibadan, Ibadan, Nigeria
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  • Charlotte I. Delage
    Affiliations
    Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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  • Marie-Ève Tremblay
    Correspondence
    Correspondence:
    Affiliations
    Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

    Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Québec City, QC, Canada

    Neurology and Neurosurgery Department, McGill University, Montréal, QC, Canada

    Department of Molecular Medicine, Université Laval, Québec City, QC, Canada

    Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada

    Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada
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  • Author Footnotes
    9 These authors contributed equally to this work
Published:January 11, 2022DOI:https://doi.org/10.1016/j.tips.2021.11.006

      Highlights

      • Distinct microglial morphological, ultrastructural, and molecular states contribute contextually relevant functions across health and disease.
      • Current microglia-related therapies, including minocycline, cytokine receptor antibodies, modulators of complement, purinergic receptors, fractalkine, colony stimulating factor1 receptor (CSF1R), and triggering receptor expressed on myeloid cells 2 (TREM2) improve the brain inflammatory balance; however, they lack selectivity on the level of microglia and/or myeloid cells needed to avoid off-targets.
      • Careful application of systemic approaches can be insightful in respect to previously less investigated microglial targets such as endocannabinoids or energetic metabolism modulators.
      • Emerging knowledge on microglial heterogeneity provides opportunity for the development of selective modulators of beneficial and/or aberrant microglial functions in a context-dependent manner.
      Microglia, brain resident immune cells, modulate development, activity, and plasticity of the central nervous system. Mechanistically implicated in numerous neurological pathologies, microglia emerge as strong contenders for novel neurotherapies. Shifting away from merely an attenuation of excessive microglial inflammatory and phagocytic activities, current therapies aim toward targeting the complex context-dependent microglial heterogeneity, unveiled by large-scale genetic studies and emerging single-cell analyses. Although lacking the necessary selectivity, initial therapies attempting to target specific state-associated microglial properties and functions (e.g., inflammatory activity, phagocytosis, proliferation, metabolism, or surveillance) are currently under pre- or even clinical (Phase I–IV) investigation. Here, we provide an update on current microglial therapeutic research and discuss what the future in the field might look like.

      Keywords

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      Glossary

      Amyloidosis
      abnormal accumulation of amyloid
      Aβ fibrillation
      formation of insoluble fibrous deposits from misfolded amyloid proteins
      Blood–brain barrier (BBB)
      neurovascular unit boundary that enables a controlled communication between the periphery and the CNS
      Border-associated macrophages (BAMs)
      nonmicroglial macrophages originating in the yolk sac and fetal liver, and populating the perivascular space or the border choroid plexus and meninges in early periods of embryonic development
      Caloric restriction
      dietary intervention based on a reduced daily caloric intake (up to 40–50%) and with a presumed mechanism of action via insulin sensitivity and glucose uptake
      Cannabinoid
      compound able to act on cannabinoid receptors, can be plant derived, synthetic or endogenous
      CD11C
      transmembrane protein expressed by leukocytes, especially dendritic cells, and involved in inflammatory responses
      CD68
      transmembrane glycoprotein utilized as a phagolysosomal marker in myeloid cells including microglia
      Endocannabinoid
      endogenous cannabinoid, primarily 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamide (anandamide, AEA)
      Exosome
      membrane-bound extracellular vesicle
      Focused ultrasound (FUS)
      minimally invasive, image-guided technology that modulates BBB permeability
      Ionized calcium binding adaptor molecule 1 (IBA1)
      actin-interacting myeloid cell/microglia protein associated with an elevated membrane ruffling and phagocytic activity
      Inflammasome
      cytoplasmic multiprotein complex of sensor proteins, inflammatory caspases, and adaptor proteins
      Ketone bodies
      water-soluble circulating lipids, such as β-hydroxybutyrate or acetoacetate, produced by the liver during low-sugar periods (e.g., low food intake, carbohydrate restricting diets) and acting as an alternative energy supply
      Major histocompatibility complex II (MHC II)
      molecules important for the initiation of antigen-specific immune response
      Microgliosis
      microglial response to a neural tissue damage, frequently associated with proliferation, elevated inflammatory mediators release and phagocytic activity
      Neurogenesis
      formation and functional maturation of new neurons
      Phagocytosis
      ingestion and elimination of solid particles (ϕ > 0.5 μm)
      Phytocannabinoids
      cannabinoids derived from the cannabis sativa plant, primarily δ9-tetrahydrocannabinol and cannabidiol
      Pinocytosis
      ingestion of liquid materials from the surroundings
      Synaptic loss
      pathological reduction of synapse density, a strong predictor of cognitive decline, sensory and motor impairment
      Synaptic pruning
      elimination of extra synaptic connections involving several mechanisms including phagocytosis, trogocytosis, and synaptic stripping
      Synthetic cannabinoids
      artificially produced cannabinoids
      Tau
      protein involved in stabilization of axonal microtubules, abundantly present in CNS neurons
      Tauopathy
      neurodegenerative disease classification involving abnormal tau protein aggregation
      Translocator protein TSPO)
      transmembrane mitochondrial protein, nonspecifically expressed by microglia and involved in immune response
      Transcytosis
      directional transport of macromolecules from one cell pole to the other