The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease

Eugenio Barone, Fabio Di Domenico, Marzia Perluigi, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD.

Original languageEnglish
Pages (from-to)16-33
Number of pages18
JournalFree Radical Biology and Medicine
Volume176
DOIs
StatePublished - Nov 20 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • AMP-Activated protein kinase
  • Alzheimer disease and type 2 diabetes
  • Biliverdin reductase-A
  • Insulin resistance
  • Neurodegeneration
  • Oxidative and nitrosative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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