title: Ribosylation triggering Alzheimer's disease-like Tau hyperphosphorylation via activation of CaMKII.
abstract: Type 2 diabetes mellitus (T2DM) is regarded as one of the serious risk factors for age-related cognitive impairment; however, a causal link between these two diseases has so far not been established. It was recently discovered that, apart from high D-glucose levels, T2DM patients also display abnormally high concentrations of uric D-ribose. Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells. However, the administration of D-glucose showed no significant changes in Tau phosphorylation under the same experimental conditions. Crucially, suppression of AGE formation using an AGEs inhibitor (aminoguanidine) effectively prevents hyperphosphorylation of Tau protein. Further study shows AGEs resulted from ribosylation activate calcium-/calmodulin-dependent protein kinase type II (CaMKII), a key kinase responsible for Tau hyperphosphorylation. These data suggest that there is indeed a mechanistic link between ribosylation and Tau hyperphosphorylation. Targeting ribosylation by inhibiting AGE formation may be a promising therapeutic strategy to prevent Alzheimer's disease-like Tau hyperphosphorylation and diabetic encephalopathies.
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Chanshuai
authors.initials: C
authors.lastname: Han
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.|Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.|Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Rongqiao
authors.initials: R
authors.lastname: He
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007701:Kinetin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D012266:Ribose / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C516978:CK59 compound; D017127:Glycation End Products, Advanced; D006146:Guanidines; C558298:Mapt protein, mouse; D016875:tau Proteins; D012266:Ribose; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose; D007701:Kinetin; C004479:pimagedine
keywords: Tau protein; hyperphosphorylation; ribosylation