Abstract
Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as “sialylation,” whereas removal by sialidases is known as “desialylation.” High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, C3, and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors CD22 and CD33 on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 (TLR4), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to TLR4 and TREM2, (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity in vivo. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.
Highlights
Microglia are brain macrophages that mediate neuroinflammation and can protect against neurodegeneration, for example, by removing protein aggregates, phagocytosing debris, and aiding repair
We have recently found that different stimuli, including LPS, fibrillar amyloid beta (Aβ) and TAU, induced desialylation of the microglial surface (Allendorf et al, 2020b)
We found that Gal-3 was highly upregulated in the brains of Alzheimer’s disease (AD) patients and 5xFAD mice, a mouse model of AD, and this increase was found in the microglia associated with amyloid plaques (Boza-Serrano et al, 2019)
Summary
Microglia are brain macrophages that mediate neuroinflammation and can protect against neurodegeneration, for example, by removing protein aggregates, phagocytosing debris, and aiding repair. The removal of sialic acid residues from the cell surface by sialidases may trigger cell signaling events as this desialylation: (i) reduces Siglec signaling, (ii) activates other receptors, (iii) decreases some gangliosides and increases others, and (iv) changes binding of lectins, opsonins, and complement. Multiple receptors, such as Toll-like receptor 4 (TLR4), can be activated by desialylation (Pshezhetsky and Ashmarina, 2013). Sumida et al (2015) reported that in the Ra2 microglial cell line, LPS caused a rapid and reversible release of a sialidase activity on exovesicles, which removed polysialic acids from the microglial surface These studies suggest that activated microglia have the potential to desialylate both themselves and surrounding neurons. What this work shows is that neuroinflammation (induced by LPS) can cause desialylation of the brain
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