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

• DOI: 10.1016/j.neurobiolaging.2014.12.033
• Publication Date: 2015-01-06T17:46:59Z
• Authors: Ermanna Turano; Giuseppe Busetto; Silvia Marconi; Flavia Guzzo; Alessia Farinazzo; Mauro Commisso; Edoardo Bistaffa; Stefano Angiari; Salvatore Musumeci; Stefano Sotgiu; Bruno Bonetti
• Keywords: Aged, 80 and over; Male; Neurons; 0301 basic medicine; Neuronal Plasticity; Polymers; Qa-SNARE Proteins; Long-Term Potentiation; Synaptophysin; Middle Aged; Hippocampus; Acetylglucosamine; 3. Good health; Mice; 03 medical and health sciences; Alzheimer Disease; Animals; Humans; Female; Microglia; Alzheimer's disease; amyloid; LTP; N-acetylglucosamine; neurotoxicity; Cells, Cultured; Aged

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.