Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation
| Autor: | Walid Soussou, Stuart A. Lipton, Scott R. McKercher, Sara Sanz-Blasco, Nima Dolatabadi, Mohd Waseem Akhtar, Rajesh Ambasudhan, Michelle S. Lee, James C. Parker, Tomohiro Nakamura, Kevin Chon |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Aging Long-Term Potentiation General Physics and Astronomy Neurodegenerative Alzheimer's Disease Hippocampus Insulysin Transgenic GTP Phosphohydrolases Synapse Mice 0302 clinical medicine 80 and over Insulin 2.1 Biological and endogenous factors Aetiology Aged 80 and over Cerebral Cortex Neurons Metabolic Syndrome Multidisciplinary Diabetes Memantine Brain Long-term potentiation Reactive Nitrogen Species Neurological NMDA receptor Female Mitochondrial fission Alzheimer's disease Microtubule-Associated Proteins Type 2 Nitroso Compounds medicine.drug Dynamins Adult medicine.medical_specialty Dendritic Spines Science Immunoblotting Induced Pluripotent Stem Cells Mice Transgenic Biology Nitric Oxide Article General Biochemistry Genetics and Molecular Biology Mitochondrial Proteins 03 medical and health sciences Oxygen Consumption Alzheimer Disease Internal medicine Diabetes Mellitus Acquired Cognitive Impairment medicine Animals Humans Metabolic and endocrine Aged Nutrition Amyloid beta-Peptides Animal Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) General Chemistry S-Nitrosylation medicine.disease Rats Brain Disorders Disease Models Animal Glucose 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Hyperglycemia Case-Control Studies Synapses Disease Models Synaptic plasticity Dementia Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 7, Iss 1, Pp 1-11 (2016) Nature communications, vol 7, iss 1 Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Alzheimer's disease is linked to metabolic syndrome and Type-2 diabetes, but the mechanism behind this association is unclear. Here, the authors show that elevated glucose and amyloid ß work together to increase nitrosative stress, leading to aberrant mitochondrial activity and synaptic dysfunction. |
| Databáze: | OpenAIRE |
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