Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain

Nona Abolhassani, Julio Leon, Zijing Sheng, Sugako Oka, Hideomi Hamasaki, Toru Iwaki, Yusaku Nakabeppu

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8-oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality lasts long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia.

Original languageEnglish
Pages (from-to)95-104
Number of pages15
JournalMechanisms of Ageing and Development
Volume161
Issue numberPt A
DOIs
Publication statusPublished - Jan 15 2017

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DNA Damage
Alzheimer Disease
Glucose
DNA Glycosylases
Brain
Mitochondrial DNA
Neurons
Cognition
Insulin
Brain Diseases
Insulin Resistance
Reactive Oxygen Species
Hippocampus
Oxidative Stress
Antioxidants
DNA
Research

All Science Journal Classification (ASJC) codes

  • Ageing
  • Developmental Biology

Cite this

Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain. / Abolhassani, Nona; Leon, Julio; Sheng, Zijing; Oka, Sugako; Hamasaki, Hideomi; Iwaki, Toru; Nakabeppu, Yusaku.

In: Mechanisms of Ageing and Development, Vol. 161, No. Pt A, 15.01.2017, p. 95-104.

Research output: Contribution to journalArticle

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