Diabetes-induced Central Neuritic Dystrophy and Cognitive Deficits Are Associated with the Formation of Oligomeric Reticulon-3 via Oxidative Stress*

Background: Diabetes induces cognitive deficits and cortical lesion. Results: Diabetes with cognitive deficits caused formation of carbonylated reticulon3 aggregates and reticulon3-immunoreactive dystrophic neurites. Conclusion: Diabetes-induced central neuritic dystrophy was correlated with formation of oligomeric reticulon3 via oxidation. Significance: Present findings concerning oxidative reticulon3 oligomers in formation of neuritic dystrophy may lead to explore a new therapeutic strategy for preventing/reducing diabetic dementia. Diabetes is a high risk factor to dementia. To investigate the molecular mechanism of diabetic dementia, we induced type 2 diabetes in rats and examined potential changes in their cognitive functions and the neural morphology of the brains. We found that the diabetic rats with an impairment of spatial learning and memory showed the occurrence of RTN3-immunoreactive dystrophic neurites in the cortex. Biochemical examinations revealed the increase of a high molecular weight form of RTN3 (HW-RTN3) in diabetic brains. The corresponding decrease of monomeric RTN3 was correlated with the reduction of its inhibitory effects on the activity of β-secretase (BACE1), a key enzyme for generation of β-amyloid peptides. The results from immunoprecipitation combined with protein carbonyl detection showed that carbonylated RTN3 was significantly higher in cortical tissues of diabetic rats compared with control rats, indicating that diabetes-induced oxidative stress led to RTN3 oxidative damage. In neuroblastoma SH-SY5Y cells, high glucose and/or H2O2 treatment significantly increased the amounts of carbonylated proteins and HW-RTN3, whereas monomeric RTN3 was reduced. Hence, we conclude that diabetes-induced cognitive deficits and central neuritic dystrophy are correlated with the formation of aggregated RTN3 via oxidative stress. We provided the first evidence that oxidative damage caused the formation of toxic RTN3 aggregates, which participated in the pathogenesis of central neuritic dystrophy in diabetic brain. Present findings may offer a new therapeutic strategy to prevent or reduce diabetic dementia.

• Publication year

  2013

• Venue

  Journal of Biological Chemistry

• Publication date

  2013-04-16

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M112.440784PMID 23592790PMCID PMC3668720
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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