Turano, Ermanna and Busetto, Giuseppe and Marconi, Silvia and Guzzo, Flavia and Farinazzo, Alessia and Commisso, Mauro and Bistaffa, Edoardo and Angiari, Stefano and Musumeci, Salvatore and Sotgiu, Stefano and Bonetti, Bruno (2015) Neurotoxicity and synaptic plasticity impairment of N-acetylglucosamine polymers: implications for Alzheimer’s disease. Neurobiology of aging, Vol. 36 (5), p. 1780-1791. ISSN 0197-4580. eISSN 1558-1497. Article.
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Here we assessed whether polymers of GlcNAc have any pathogenetic role in 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 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 which 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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