Increasing phagocytosis of microglia by targeting CD33 with liposomes displaying glycan ligands

Bhattacherjee, Abhishek; Daskhan, Gour Chand; Bains, Arjun; Watson, Adrianne Eve Scovil; Eskandari-Sedighi, Ghazaleh; Laurent, Chris D. St.; Voronova, Anastassia; Macauley, Matthew

doi:10.1016/j.jconrel.2021.09.010

Cited by 17 publications

(7 citation statements)

References 58 publications

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“…As Siglecs are endocytic receptors 52 , we investigated if Siglec-6 can internalize cargo such as EVs. Using Daudi cells, a human B-cell line, transduced to overexpress Siglec-6, we assessed internalization of 5 nGLLs formulated with a pHrodo-labeled lipid ( 13 ), which increases fluorescence once within the acidic endosomal compartment, thereby reporting on cellular internalization 53 . A time-dependent increase in pHrodo signal for 5 nGLLs was observed independent of Arg122 and only at 37 °C, which is indicative of cellular internalization (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket

et al. 2023

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Immunomodulatory Siglecs are controlled by their glycoprotein and glycolipid ligands. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer, missing the complex behaviors of glycolipids in a membrane. Through optimizing a liposomal formulation to dissect Siglec–glycolipid interactions, it is shown that Siglec-6 can recognize glycolipids independent of its canonical binding pocket, suggesting that Siglec-6 possesses a secondary binding pocket tailored for recognizing glycolipids in a bilayer. A panel of synthetic neoglycolipids is used to probe the specificity of this glycolipid binding pocket on Siglec-6, leading to the development of a neoglycolipid with higher avidity for Siglec-6 compared to natural glycolipids. This neoglycolipid facilitates the delivery of liposomes to Siglec-6 on human mast cells, memory B-cells and placental syncytiotrophoblasts. A physiological relevance for glycolipid recognition by Siglec-6 is revealed for the binding and internalization of extracellular vesicles. These results demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.

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Section: Resultsmentioning

confidence: 99%

Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket

et al. 2023

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“…CD33 overexpression in the human brain is associated with impaired cognition 45 , 47 , 48 . When alpha-2,3 and, preferentially, alpha-2,6 sialylated glycans bind CD33, the Aβ phagocytosis activity of microglia increases 11 , 49 , 50 . Importantly, ST6GALNACs only modify GalNAc residues found on O -glycans and glycosphingolipids, highlighting the need for future studies focused on the sialylation changes in O -glycans and glycosphingolipids in AD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and glycomic analyses highlight pathway-specific glycosylation alterations unique to Alzheimer’s disease

Tang

Tena

Lucente

et al. 2023

Sci Rep

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Glycosylation has been found to be altered in the brains of individuals with Alzheimer’s disease (AD). However, it is unknown which specific glycosylation-related pathways are altered in AD dementia. Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified glycosylation-related genes ubiquitously changed in individuals with AD. Several differentially expressed glycosyltransferases found by RNA-seq were confirmed by qPCR in a different set of human medial temporal cortex (MTC) samples (n = 20 AD vs. 20 controls). N-glycan-related changes predicted by expression changes in these glycosyltransferases were confirmed by mass spectrometry (MS)-based N-glycan analysis in the MTC (n = 9 AD vs. 6 controls). About 80% of glycosylation-related genes were differentially expressed in at least one brain region of AD participants (adjusted p-values < 0.05). Upregulation of MGAT1 and B4GALT1 involved in complex N-linked glycan formation and galactosylation, respectively, were reflected by increased concentrations of corresponding N-glycans. Isozyme-specific changes were observed in expression of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family and the alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase (ST6GALNAC) family of enzymes. Several glycolipid-specific genes (UGT8, PIGM) were upregulated. The critical transcription factors regulating the expression of N-glycosylation and elongation genes were predicted and found to include STAT1 and HSF5. The miRNA predicted to be involved in regulating N-glycosylation and elongation glycosyltransferases were has-miR-1-3p and has-miR-16-5p, respectively. Our findings provide an overview of glycosylation pathways affected by AD and potential regulators of glycosyltransferase expression that deserve further validation and suggest that glycosylation changes occurring in the brains of AD dementia individuals are highly pathway-specific and unique to AD.

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“…The researchers found that this effect is associated with the loss of CD33 from the cell surface and the internalization of liposomes. Notably, this study demonstrates that the multivalent engagement of CD33 with glycan ligands can modulate microglial cell function, offering a promising strategy for treating neurodegeneration, particularly AD [ 47 ]. Tentillier et al investigated the potential of CD163-targeted glucocorticoids to protect dopaminergic neurons in a 6-hydroxydopamine PD model in rats.…”

Section: Lipidic Nanoparticles Against Neurodegenerationmentioning

confidence: 99%

Lipidic Nanoparticles, Extracellular Vesicles and Hybrid Platforms as Advanced Medicinal Products: Future Therapeutic Prospects for Neurodegenerative Diseases

Tsakiri,

Tsichlis,

Zivko

et al. 2024

Pharmaceutics

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Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, affect a wide variety of the population and pose significant challenges with progressive and irreversible neural cell loss. The limitations of brain-targeting therapies and the unclear molecular mechanisms driving neurodegeneration hamper the possibility of developing successful treatment options. Thus, nanoscale drug delivery platforms offer a promising solution. This paper explores and compares lipidic nanoparticles, extracellular vesicles (EVs), and hybrid liposomal–EV nanoplatforms as advanced approaches for targeted delivery to combat neurodegeneration. Lipidic nanoparticles are well-characterized platforms that allow multi-drug loading and scalable production. Conversely, EVs offer the ability of selectively targeting specific tissues and high biocompatibility. The combination of these two platforms in one could lead to promising results in the treatment of neurodegeneration. However, many issues, such as the regulatory framework, remain to be solved before these novel products are translated into clinical practice.

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Increasing phagocytosis of microglia by targeting CD33 with liposomes displaying glycan ligands

Cited by 17 publications

References 58 publications

Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket

Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket

Transcriptomic and glycomic analyses highlight pathway-specific glycosylation alterations unique to Alzheimer’s disease

Lipidic Nanoparticles, Extracellular Vesicles and Hybrid Platforms as Advanced Medicinal Products: Future Therapeutic Prospects for Neurodegenerative Diseases

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