Table 1 Therapeutic molecules for microglia modulation in different neurological disease models
From: Taming microglia: the promise of engineered microglia in treating neurological diseases
| Â | Microglial targets | Disease models | Animals | Working mechanisms and effects on microglia | Refs. |
|---|---|---|---|---|---|
IL-12 | IL-12R | Glioblastoma multiforme | Rat | Long-lasting expression of IL-12 increased infiltration of activated microglia to the tumour, inhibiting the tumour growth and increasing the survival of tumour-bearing rats | [107] |
(Astrocytic) IL-3 | IL-3R | Alzheimer’s disease | 5xFAD mice and human samples | Aβ deposits induced microglia to upregulate IL-3Rα, the receptor for IL-3, to become more responsive to IL-3, constitutively produced by astrocytes. The IL-3–IL-3Rα interaction induced reprogramming in microglia, enhancing their ability to cluster and clear misfolded protein aggregates (e.g. Aβ and tau). In vitro, the pathology and cognitive functions in AD mice were improved. Increasing IL-3 or upregulating IL-3Rα expression might be promising therapeutic targets for AD treatment | [108] |
IFN-γ | IFN-γR | Alzheimer’s disease | AD transgenic mice | Chronic exposure to Aβ induced metabolic defects in microglia, making them tolerant to Aβ. Chronic IFN-γ treatment restored the immunological functions of microglia, and mitigated AD-like pathology and improved cognitive functions in mice | [109] |
Anti-pyroglutamate-3 Aβ antibodies | pyroglutamate-3 Aβ | Alzheimer’s disease | Mice | Pyroglutamate-3 Aβ (pGlu-3 Aβ) is a post-translationally modified Aβ species associated with Alzheimer’s disease (AD). Anti-pGlu-3 Aβ antibodies resulted in more plaque-associated microglia for Aβ clearance | [110] |
TREM 2 antibodies | TREM2 | Frontotemporal lobe degeneration | Grn KO mice (progranulin deficiency model) | Antagonistic TREM2 antibodies enhanced TREM2 shedding, reducing its signalling in microglia. As a result, microglial hyperactivation and phagocytic activities were ameliorated. However, this did not attenuate neurotoxicity. It turned out that TREM2-dependant microglia hyperactivation was neuroprotective. TREM2 agonists might be a therapeutic strategy in this pathological context | [111] |
Anti-miR-155 inhibitor | miR-155 | Amyotrophic lateral sclerosis (ALS) | SOD1 mice | Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates ALS symptoms | [112] |
LncRNA GAS5 inhibitor | LncRNA GAS5 | Multiple sclerosis | EAE mice | LncRNA GAS5 potently inhibit microglial M2 polarisation, by binding to PRC2 to suppress IRF4 transcription. LncRNA GAS5 inhibitors promote M1 polarisation, attenuating EAE severeness and promoting remyelination | [113] |
HDAC inhibitors (Scriptaid) | Histone deacetylase inhibitor (HDAC) | Severe traumatic brain injury (TBI) | Mice with TBI | Scriptaid upregulated microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signalling, an intracellular signal pathway that promotes cell survival and proliferation, and polarizing microglia towards M2. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction | [114] |
Chlorogenic acid (CGA) | Â MIR497HG/miR-29b-3p/SIRT1 Axis | Oxygen and glucose deprivation (OGD)-elicited neuroinflammation | Cell culture | CGA attenuated OGD-mediated neuroinflammation and oxidative stress in microglia and inhibited microglia-mediated neuronal apoptosis. CGA increased the levels of MIR497HG and SIRT1 and suppressed the levels of miR-29b-3p in BV2 and HT-22 cells | [115] |
Sialic acid mimetic |  CD33 | Alzheimer’s disease | Cell culture | The sialic acid mimetic bound to CD33, a cell surface receptor, and increased the uptake of Alzheimer peptide into microglia | [116] |