Neurotoxicity and synaptic plasticity impairment of N-acetylglucosamine polymers: implications for Alzheimer's disease

Neurobiology of Aging
Ermanna TuranoBruno Bonetti

Abstract

We assessed whether polymers of N-acetylglucosamine (GlcNAc) have any pathogenetic role in Alzheimer's disease (AD). First, by using specific dyes, we found deposits of polymers of GlcNAc in sporadic but not in familial AD. We found that neurons and microglia exposed to GlcNAc and uridine diphosphate (UDP)-GlcNAc are able to form GlcNAc polymers, which display a significant neurotoxicity in vitro. Moreover, the exposure of organotypic hippocampal cultures to the same compounds led to synaptic impairment with decreased levels of syntaxin and synaptophysin. In addition, acute hippocampal slices treated with GlcNAc/UDP-GlcNAc showed a clear reduction of long-term potentiation of excitatory synapses. Finally, we demonstrated that microglial cells are able to phagocytose chitin particles and, when exposed to GlcNAc/UDP-GlcNAc, show cellular activation and intracellular deposition of GlcNAc polymers that are eventually released in the extracellular space. Taken together, our results indicate that both microglia and neurons produce GlcNAc polymers, which trigger neurotoxicity both directly and through microglia activation. GlcNAc polymer-driven neurotoxicity offers novel pathogenic insights in sporadic AD and new therapeutic options.

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Citations

Nov 4, 2015·Brain, Behavior, and Immunity·Fan SuZhijun Zhang
Dec 13, 2018·Neural Regeneration Research·Mostafa M Ibrahim, Moustafa T Gabr
Oct 2, 2019·Neural Regeneration Research·Bettina M Foidl, Christian Humpel
Jun 2, 2020·Frontiers in Aging Neuroscience·Yunying Yang, Zhentao Zhang
Oct 5, 2018·Journal of Alzheimer's Disease : JAD·Christine LomiguenRobert Stern
Dec 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Saravut Satitsri, Chatchai Muanprasat

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