Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments

Varbanov, Hristo; Jia, Shaobo; Kochlamazashvili, Gaga; Bhattacharya, Subhrajit; Buabeid, Manal; Tabbal, Mohamed El; Hayani, Hussam; Stoyanov, Stoyan; Sun, Wei-Lun; Thiesler, Hauke; Röckle, Iris; Hildebrandt, Herbert; Senkov, Oleg; Suppiramaniam, Vishnu; Gerardy‐Schahn, Rita; Dityatev, Alexander

doi:10.1016/j.nbd.2023.106079

Cited by 9 publications

(9 citation statements)

References 81 publications

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“…Furthermore, intranasally applied soluble polysialic acid with a degree of polymerization 12 (polySia DP12) restored the synaptic activity in the prefrontal cortex of mice deficient in a polysialic acid-producing enzyme. Interestingly, the treatment with polySia DP12 also ameliorated the impaired cognitive performance observed in the polysialic acid-producing enzyme-deficient mice and in two animal models of Alzheimer’s disease ( 155 ). Moreover, in a study conducted with double transgenic AD (2 × Tg-AD) mice, sialic acid was added to the mouse chow as a form of treatment ( 156 ).…”

Section: Main Textmentioning

confidence: 99%

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Wißfeld,

Abou Assale,

Cuevas-Rios

et al. 2024

Front. Neurol.

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Sialic acids, commonly found as the terminal carbohydrate on the glycocalyx of mammalian cells, are pivotal checkpoint inhibitors of the innate immune system, particularly within the central nervous system (CNS). Sialic acid-binding immunoglobulin-like lectins (SIGLECs) expressed on microglia are key players in maintaining microglial homeostasis by recognizing intact sialylation. The finely balanced sialic acid-SIGLEC system ensures the prevention of excessive and detrimental immune responses in the CNS. However, loss of sialylation and SIGLEC receptor dysfunctions contribute to several chronic CNS diseases. Genetic variants of SIGLEC3/CD33, SIGLEC11, and SIGLEC14 have been associated with neurodegenerative diseases such as Alzheimer’s disease, while sialyltransferase ST8SIA2 and SIGLEC4/MAG have been linked to psychiatric diseases such as schizophrenia, bipolar disorders, and autism spectrum disorders. Consequently, immune-modulatory functions of polysialic acids and SIGLEC binding antibodies have been exploited experimentally in animal models of Alzheimer’s disease and inflammation-induced CNS tissue damage, including retinal damage. While the potential of these therapeutic approaches is evident, only a few therapies to target either sialylation or SIGLEC receptors have been tested in patient clinical trials. Here, we provide an overview of the critical role played by the sialic acid-SIGLEC axis in shaping microglial activation and function within the context of neurodegeneration and synaptopathies and discuss the current landscape of therapies that target sialylation or SIGLECs.

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Section: Main Textmentioning

confidence: 99%

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Wißfeld,

Abou Assale,

Cuevas-Rios

et al. 2024

Front. Neurol.

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“…Polysialic acid fragments have also been delivered through the intranasal route to the brains of mice who are deficient in polysia and in two mouse models of Alzheimer's disease [151]. Alzheimer's disease and schizophrenia have been associated with a deficit of neural cell adhesion molecule (NCAM), which is the brain's main repository of polysialic acid.…”

Section: Naked Polysialic Acid Not Feasible As Pharmaceuticalsmentioning

confidence: 99%

“…Alzheimer's disease and schizophrenia have been associated with a deficit of neural cell adhesion molecule (NCAM), which is the brain's main repository of polysialic acid. While mice receiving this treatment were shown to have rescued medial prefrontal cortex tasks, studies of intracranial pharmacokinetics demonstrated that these particles were only sparsely distributed in the mouse brain after 3 h and declined rapidly by 24 h [151].…”

Section: Naked Polysialic Acid Not Feasible As Pharmaceuticalsmentioning

confidence: 99%

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration

Tolentino,

Tolentino

et al. 2023

Pharmaceuticals

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Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte-derived macrophages (PBMDMs) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring glyco-immune checkpoint control with a sialic acid mimetic agonist targeting microglial/macrophage Siglecs to regain retinal para-inflammatory and inflammatory homeostasis is a promising therapeutic that could halt the progression of and improve visual function in all stages of macular degeneration.

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“…Polysialylation was also shown to reduce immunogenicity and antigenicity of protein enzymes like asparaginase [30]. PSA mimetics have been demonstrated in experimental models to promote therapeutic effect in spinal cord injury, [31,32] PSA also shows benefit in animal models of macular degeneration and Alzheimer's [33,34].…”

Section: Samp Mimetics Promising Immune Modulating Therapeuticsmentioning

confidence: 99%

SIGLECs the Main Self-Pattern Recognition Receptors of the Immune System. A Promising Target for Inflammatory Modulation

Tolentino

2023

AJBSR

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The existence of a Self-Pattern Recognition Receptor(sPRR) was postulated over 3 decades ago which would recognize and prevent immune response to self-cells covered with Self-Associated Molecular Patterns (SAMP). In the last few years, it has become evident that SAMPS are glycan patterns with end sialylation that activate complement factor H to deamplify the complement pathway and agonize immune resolving sialic acid binding Ig like lectins (Siglecs). The latter resolves inflammation via localized recruitment of a potent protein tyrosine phosphatase which dephosphorylates intracytoplasmic tyrosine kinase dependent activation pathways within immune cells. This mini review will recount the history behind this discovery and explain how SAMP mimetics can be used to therapeutically modulate the immune system.

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Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments

Cited by 9 publications

References 81 publications

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases

Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration

SIGLECs the Main Self-Pattern Recognition Receptors of the Immune System. A Promising Target for Inflammatory Modulation

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