Neurotoxicity and synaptic plasticity impairment of N-acetylglucosamine polymers: implications for Alzheimer's disease.
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.
Section of Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
Ermanna
E
Turano
Section of Physiology and Psychology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy; Italian Institute of Neuroscience, Verona, Italy.
Giuseppe
G
Busetto
Section of Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
Silvia
S
Marconi
Department of Biotechnology, University of Verona, Verona, Italy.
Flavia
F
Guzzo
Section of Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
Alessia
A
Farinazzo
Department of Biotechnology, University of Verona, Verona, Italy.
Mauro
M
Commisso
Section of Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
Edoardo
E
Bistaffa
Department of Pathology, University of Verona, Verona, Italy.
Stefano
S
Angiari
Department of Biomolecular Chemistry, National Research Council, Catania, Italy.
Salvatore
S
Musumeci
Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
Stefano
S
Sotgiu
Section of Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy. Electronic address: bruno.bonetti@univr.it.
Bruno
B
Bonetti
D000117:Acetylglucosamine / Q000378:metabolism* / Q000633:toxicity*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism*; D011108:Polymers; D050765:Qa-SNARE Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
D011108:Polymers; D050765:Qa-SNARE Proteins; D016708:Synaptophysin; D000117:Acetylglucosamine
Alzheimer's disease; Amyloid; LTP; N-acetylglucosamine; Neurotoxicity