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

NEUROBIOLOGY OF AGING

卷:36

Article

Turano, Ermanna¹  Busetto, Giuseppe^2,3  Marconi, Silvia¹  Guzzo, Flavia⁴  Farinazzo, Alessia¹  Commisso, Mauro⁴  Bistaffa, Edoardo¹  Angiari, Stefano⁵  Musumeci, Salvatore⁶  Sotgiu, Stefano⁷  Bonetti, Bruno¹ 

[1] Univ Verona, Neurol Sect, Dept Neurol & Movement Sci, I-37134 Verona, Italy

[2] Univ Verona, Sect Physiol & Psychol, Dept Neurol & Movement Sci, I-37134 Verona, Italy

[3] Italian Inst Neurosci, Verona, Italy

[4] Univ Verona, Dept Biotechnol, I-37134 Verona, Italy

[5] Univ Verona, Dept Pathol, I-37134 Verona, Italy

[6] CNR, Dept Biomol Chem, Catania, Italy

[7] Univ Sassari, Dept Clin & Expt Med, I-07100 Sassari, Italy

关键词: Alzheimer's disease;    N-acetylglucosamine;    Amyloid;    Neurotoxicity;    LTP;   

DOI  :  10.1016/j.neurobiolaging.2014.12.033

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

Free