title: Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy.
abstract: Neurofibrillary tangles (NFT), mainly consisting of fibrillar aggregates of hyperphosphorylated tau, are a defining pathological feature of Alzheimer's Disease and other tauopathies. Progressive accumulation of tau into NFT is considered to be a toxic cellular event causing neurodegeneration. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification and O-GlcNAcylation of tau has been suggested to regulate tau phosphorylation. We tested if an increase in tau O-GlcNAcylation affected tau phosphorylation and aggregation in the rTg4510 tau transgenic mouse model. Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau. This indicates that O-GlcNAcylation prevents the aggregation of tau in a manner that does not affect its normal phosphorylation state. Collectively, our results support O-GlcNAcase inhibition as a potential therapeutic strategy for the treatment of Alzheimer's Disease and other tauopathies.
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA.
authors: Danielle L
authors: DL
authors: Graham
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA.
authors: Audrey J
authors: AJ
authors: Gray
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA.
authors: John A
authors: JA
authors: Joyce
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA.
authors: Dongzi
authors: D
authors: Yu
authors: McLaughlin Research Institute, Great Falls, MT 59405, USA.
authors: Jill
authors: J
authors: O'Moore
authors: McLaughlin Research Institute, Great Falls, MT 59405, USA.
authors: George A
authors: GA
authors: Carlson
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA.
authors: Mark S
authors: MS
authors: Shearman
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA.
authors: Tammy L
authors: TL
authors: Dellovade
authors: EMD Serono Research & Development Institute, Billerica, MA 01821, USA. Electronic address: heike.hering@emdserono.com.
authors: Heike
authors: H
authors: Hering
mesh_terms: D000117:Acetylglucosamine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006031:Glycosylation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011714:Pyrans / Q000494:pharmacology*; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D011714:Pyrans; D013844:Thiazoles; D016875:tau Proteins; C572247:thiamet G; D000117:Acetylglucosamine
keywords: Alzheimer's Disease; O-GlcNAc; O-tau(S400) antibody; OGA; Tau aggregation; ThiametG; rTg4510