title: Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation.
abstract: Metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM) increase risk for Alzheimer's disease (AD). The molecular mechanism for this association remains poorly defined. Here we report in human and rodent tissues that elevated glucose, as found in MetS/T2DM, and oligomeric β-amyloid (Aβ) peptide, thought to be a key mediator of AD, coordinately increase neuronal Ca(2+) and nitric oxide (NO) in an NMDA receptor-dependent manner. The increase in NO results in S-nitrosylation of insulin-degrading enzyme (IDE) and dynamin-related protein 1 (Drp1), thus inhibiting insulin and Aβ catabolism as well as hyperactivating mitochondrial fission machinery. Consequent elevation in Aβ levels and compromise in mitochondrial bioenergetics result in dysfunctional synaptic plasticity and synapse loss in cortical and hippocampal neurons. The NMDA receptor antagonist memantine attenuates these effects. Our studies show that redox-mediated posttranslational modification of brain proteins link Aβ and hyperglycaemia to cognitive dysfunction in MetS/T2DM and AD.
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.
authors.forename: Mohd Waseem
authors.initials: MW
authors.lastname: Akhtar
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Sanz-Blasco
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Dolatabadi
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: James
authors.initials: J
authors.lastname: Parker
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chon
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Quantum Applied Science and Research, 5754 Pacific Center Blvd. Suite 203b, San Diego, California 92121, USA.
authors.forename: Walid
authors.initials: W
authors.lastname: Soussou
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ambasudhan
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, California 92121, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Avenue, La Jolla, California 92037, USA.|Neurodegenerative Disease Center, Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, California 92121, USA.|Department of Neurosciences, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D015151:Immunoblotting; D057026:Induced Pluripotent Stem Cells; D007328:Insulin / Q000378:metabolism; D007339:Insulysin / Q000378:metabolism*; D017774:Long-Term Potentiation; D008297:Male; D008559:Memantine / Q000494:pharmacology; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism*; D010101:Oxygen Consumption; D051381:Rats; D026361:Reactive Nitrogen Species; D013569:Synapses / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D007328:Insulin; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009603:Nitroso Compounds; D026361:Reactive Nitrogen Species; D009569:Nitric Oxide; D007339:Insulysin; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C486391:Dnm1l protein, mouse; C519851:Dnm1l protein, rat; D034281:Dynamins; D005947:Glucose; D008559:Memantine