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

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