NEW YORK (Reuters Health) - Impaired insulin signaling in the brain is associated with Alzheimer’s disease, which may represent a “type 3" diabetes, according to a report in the March Journal of Alzheimer’s Disease.
“Alzheimer’s disease can be linked to insulin-related metabolic and signaling abnormalities in the brain,” Dr. Suzanne M. de la Monte from Brown Medical School, Providence, Rhode Island told Reuters Health. “In some respects, this concept is not far removed from previous work in the field where investigators demonstrated that some of the earliest abnormalities in brains with Alzheimer’s disease include reduced glucose utilization and energy metabolism.”
Dr. de la Monte and colleagues investigated Alzheimer’s disease-associated abnormalities in insulin and insulin-like growth factor (IGF) peptide and receptor gene expression, as well as the downstream signaling mechanisms that mediate neuronal survival, using postmortem brain tissue from 28 patients with Alzheimer’s disease and 26 controls.
The mean levels of insulin and IGF-I receptor mRNA transcripts in the hippocampus and hypothalamus were 8- to 10-fold lower in Alzheimer’s disease brains than in control brains, the authors report.
Insulin gene expression in cerebellar tissue was also significantly lower in Alzheimer’s disease relative to control cases, the report indicates.
The researchers further note both reduced levels of insulin receptor substrate (IRS)-1 expression and impaired signaling through IRS-1 molecules. “Since insulin and IGF-I transmit pro-survival and pro-growth signaling through IRS molecules,” they write, “the reduced levels of IRS expression could contribute to growth factor resistance in the CNS.”
The studies also demonstrated significantly reduced levels of tau and significantly increased levels of amyloid-beta precursor peptide mRNA transcripts in Alzheimer’s disease compared with control cases.
“Our study demonstrates substantially reduced levels of insulin and insulin receptors in brains with Alzheimer’s disease,” Dr. de la Monte said. “We now have substantial evidence that the abnormality occurs early in the course of Alzheimer’s disease.”
“These abnormalities resemble a kind of diabetes of the brain, but they are not related to” types 1 or 2 diabetes, Dr. de la Monte explained. “We also have no evidence that individuals with type 1 or type 2 diabetes are at any greater risk of developing Alzheimer’s disease than are individuals who do not have diabetes.”
“In other words,” Dr. de la Monte said, “brain diabetes (type 3) is a separate and distinct entity. The implication is that treating peripheral (type 1 or type 2) diabetes may have no impact on Alzheimer’s disease.”
“We believe that therapeutic agents need to be designed that specifically influence the actions of insulin in the brain,” Dr. de la Monte concluded.
J Alzheimer’s Dis 2005;7:63-80.
MeSH Headings:Membrane Proteins: Receptors, Cell Surface: Receptors, Somatomedin: Receptor, IGF Type 1: Receptors, Growth Factor: Receptors, PeptideCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
