CRITICAL ROLE OF BRAIN-SPECIFIC GANGLIOSIDES IN THE PATHOGENESIS OF TRAUMATIC BRAIN INJURY AND ALZHEIMER’S DISEASE
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Date
2020
Authors
Ponomarev, Eugene D.
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International conference "MODERN PERSPECTIVES FOR BIOMEDICAL SCIENCES: FROM BENCH TO BEDSIDE”; National Laboratory Astana
Abstract
Major brain glycosphingolipids, also called brain gangliosides, are localized within neuronal lipid rafts
(NLR) of neuronal axons and synapses and their role in neurodegenerative diseases remains unknown.
Here, we compared the outcome of traumatic brain injury (TBI) and Alzheimer’s disease (AD) pathology
in wild-type and glycosphingolipid-deficient animals. The St3gal5 gene encodes for ST3 β-galactoside
alpha-2, 3-sialyltransferase 5, which is responsible for the biosynthesis of complex a- and b- and c- series
gangliosides in the brain. We found that uninjured st3gal5-deficient mice exhibit normal cognitive and
social behaviors, but do exhibit some very mild motor deficits. After TBI, st3gal5-deficient animals exhibit
marked deficits in cognitive and motor functions, which was associated with increased hemorrhage and
neuronal damage owing to the failure of NLR-induced platelet activation and serotonin (5-HT) secretion.
The decrease in NLR-induced platelet-derived platelet activating factor (PAF) release also resulted in reduced
microglial activation and central nervous system macrophage infiltration in the st3gal5-deficient
animals after TBI. Further investigation demonstrated that the interaction of platelets with NLR stimulated
neurite growth, increased the number of dendritic spines, and increased neuronal activity during
TBI. To understand the role of gangliosides in Alzheimer’s disease pathology we crossed st3gal5-deficient
mice with 5XFAD transgenic mice that overexpress three mutant human amyloid proteins AP695 and
two presenilin PS1genes. We found that st3gal5-deficient 5XFAD mice had a significantly reduced burden
of amyloid depositions, low level of neuroinflammation, and did not exhibit neuronal loss or synaptic
dysfunction as compared to wild-type 5XFAD mice. St3gal5-deficient 5XFAD mice also performed significantly
better in a cognitive test than wild-type 5XFAD control group. Finally, the treatment of wild-type
5XFAD mice with the sialic acid-specific Limax flavus lectin resulted in substantial improvement of AD
pathology. Thus, our study establishes an important role for major brain glycolipids in the regulation of
neuroinflammation, neuronal plasticity, synaptic functions and cognitive ability after a neuronal injury
during TBI- and AD-related neurodegeneration.
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Keywords
Alzheimer’s disease, Research Subject Categories::MEDICINE, traumatic brain injury, brain-specific gangliosides, neuroinflammation