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Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation

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  • Mohd Waseem Akhtar

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute)

  • Sara Sanz-Blasco

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Present address: Instituto de Investigaciones Farmacológicas (ININFA) CONICET—UBA Junín 956 5to Piso, 1113 Buenos Aires, Argentina.)

  • Nima Dolatabadi

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Neurodegenerative Disease Center, Scintillon Institute)

  • James Parker

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Neurodegenerative Disease Center, Scintillon Institute)

  • Kevin Chon

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute)

  • Michelle S. Lee

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute)

  • Walid Soussou

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Quantum Applied Science and Research)

  • Scott R. McKercher

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Neurodegenerative Disease Center, Scintillon Institute)

  • Rajesh Ambasudhan

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Neurodegenerative Disease Center, Scintillon Institute)

  • Tomohiro Nakamura

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Neurodegenerative Disease Center, Scintillon Institute)

  • Stuart A. Lipton

    (Center for Neuroscience and Aging Research, Sanford Burnham Prebys Medical Discovery Institute
    Neurodegenerative Disease Center, Scintillon Institute
    University of California, San Diego, School of Medicine)

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 Ca2+ 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.

Suggested Citation

  • Mohd Waseem Akhtar & Sara Sanz-Blasco & Nima Dolatabadi & James Parker & Kevin Chon & Michelle S. Lee & Walid Soussou & Scott R. McKercher & Rajesh Ambasudhan & Tomohiro Nakamura & Stuart A. Lipton, 2016. "Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10242
    DOI: 10.1038/ncomms10242
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