Authors: Neumann, Karen F.; Rojo, Leonel; Navarrete, Leonardo P.; Farias, Gonzalo; Reyes, Paula; Maccioni, Ricardo B.

Source: Current Alzheimer Research, Volume 5, Number 5, October 2008 , pp. 438-447(10)

Publisher: Bentham Science Publishers

Abstract:

Hyperinsulinemia as well as type II diabetes mellitus are among the risk factors for Alzheimer's disease (AD). However, the molecular and cellular basis that link insulin resistance disorders and diabetes with AD are far from clear. Here, we discuss the potential molecular mechanisms that may explain the participation of these metabolic disorders in the pathogenesis of AD. The human brain uses glucose as a primary fuel; insulin secreted by the pancreas cross the bloodbrain barrier (BBB), reaching neurons and glial cells, and exerts a region-specific effect on glucose metabolism. Glucose homeostasis is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter regulation, cell survival and synaptic plasticity. It also plays a key role in cognitive function. In an insulin resistance condition, there is a reduced sensitivity to insulin resulting in hyperinsulinemia; this condition persists for several years before becoming fullblown diabetes. Toxic levels of insulin negatively influence neuronal function and survival, and elevation of peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative phenotype and decline in cognitive function. Chronic peripheral hyperinsulinemia results in a reduction of insulin transport across the BBB and a reduced insulin signaling in brain, altering all of insulin's actions, including its anti-apoptotic effect. However, the increase in brain insulin levels resulting from its peripheral administration at optimal doses has shown a cognitionenhancing effect in patient with AD. Some drugs utilized in type II diabetes mellitus reduce cognitive impairment associated with AD. The link between insulin resistance and neurodegeneration and AD, and the possible therapeutic targets in preventing the insulin-resistance disorders are analyzed.

Keywords: Insulin; insulin resistance; hyperinsulinemia; diabetes; cognition; neurodegeneration; Alzheimer's disease

Document Type: Research article

DOI: http://dx.doi.org/10.2174/156720508785908919

Publication date: 2008-10-01

More about this publication?

• Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

Related content

• In this: publication
• By this: publisher
• In this Subject: Neurology & Psychiatry ,  Pathology
• By this author: Neumann, Karen F. ;  Rojo, Leonel ;  Navarrete, Leonardo P. ;  Farias, Gonzalo ;  Reyes, Paula ;  Maccioni, Ricardo B.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers