The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer´s Disease.
Alzheimer´s disease is a chronic neurodegenerative disorder affecting millions of people worldwide, characterized by a progressive decline in cognitive functions. Factors involved in the pathogenesis of Alzheimer´s disease include metabolic alterations such as insulin resistance and hyperglycemia, both of which are also hallmarks of type-2 diabetes mellitus. The accumulation of β-amyloid peptides in the brain of Alzheimer´s patients is responsible in part for the neurotoxicity underlying the loss of synaptic plasticity that triggers a cascade of events leading to cell death. A large number of studies revealed the key role of the hippocampus and cerebral cortex in the memory and learning deficits of Alzheimer´s disease. Although ample evidence suggests a link between altered insulin action, the dysregulation of glucose metabolism, and β-amyloid accumulation in animal models and humans with Alzheimer´s, no supporting evidence was available. In this article, we review the potential toxic effects of β-amyloid in the hypothalamus, a brain center involved in the control of insulin action and glucose metabolism. Furthermore, we discuss our recent studies unraveling a novel neurotoxic action of β-amyloid that perturbs hypothalamic glucoregulation, leading to increased hepatic glucose production and hyperglycemia. These findings provide evidence for a link between β-amyloid toxicity and altered glucose metabolism.
Department of Basic Research, National Institute of Geriatrics, Mexico City, Mexico.
Isabel
I
Arrieta-Cruz
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
Roger
R
Gutiérrez-Juárez
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance
D016229:Amyloid beta-Peptides; D007328:Insulin; D005947:Glucose