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Links between obesity/diabetes & Alzheimer disease: Diet-induced insulin resistance shown to increase CNS beta-amyloid levels and worsens cognition in a model of Alzheimer disease

Posted on: 05 Apr 04
Links between obesity/diabetes & Alzheimer disease: Diet-induced insulin resistance shown to increase CNS beta-amyloid levels and worsens cognition in a model of Alzheimer disease

Summary

DailyUpdates 5th April: There is growing evidence of a link between type-2 diabetes/obesity and Alzheimer disease. Researchers now report that diet-induced insulin resistance increases beta amyloid generation, amyloid plaque burden in the brain and behavioural impairment in a model of Alzheimer disease.

DailyUpdates 5th April: There is growing evidence of a link between type-2 diabetes/obesity and Alzheimer disease.  Researchers now report that diet-induced insulin resistance increases beta amyloid generation,  amyloid plaque burden in the brain and behavioural impairment in a model of Alzheimer disease. 


The aging population will contribute to an expansion of the already $30 billion neurodegenerative market. The market for Alzheimer disease therapy is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Between 2005 and 2010, drugs for treating Alzheimer disease could achieve sales of well over $2 billion (for a full analysis of this field click here). 


A second condition that has dramatically increased in incidence over the past decade is diabetes which, according to WHO currently affects some 130 million people world-wide, a figure that is predicted to increase to 300 million by 2025. The majority of patients suffer from type 2 diabetes.  The global market for diabetes therapeutics reportedly topped $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months (for a full analysis of diabetes therapeutics and market opportunities click here).

 

An evolving concept is that diabetes is a risk factor for developing Alzheimer disease. Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid beta protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively and a recent study has demonstrated that type 2 diabetes is twice as prevalent in Alzheimer disease versus non-Alzheimer disease controls.

 

The reason for diabetes being a risk fact for Alzheimer disease is unclear however increased beta-amyloid (Abeta) aggregation through inhibition of insulin-degrading enzyme is one hypothesis. Insulin-degrading enzyme (IDE) has been identified as a principal regulator of Abeta levels in neuronal and microglial cells and human genetic studies have implicated the Insulin-degrading enzyme region of chromosome 10 in both Alzheimer disease and type 2 diabetes.  In a recent American Journal of Pathology article, Farris et al report that naturally occurring IDE missense mutations in a well-characterized rat model of type 2 diabetes mellitus result in decreased catalytic efficiency and a 15 to 30% deficit in the degradation of both insulin and Abeta. Endogenously secreted Abeta(40) and Abeta(42) are significantly elevated in primary neuronal cultures from animals with the IDE mutations although in these animals compensatory mechanisms appeared to prevent the in vivo build up of Abeta.


In their upcoming Faseb Journal article Ho et al report that diet-induced insulin resistance increases amyloidogenic beta-amyloid Abeta1-40 and Abeta1-42 peptide generation in the brain of Tg2576 mice, which model Alzheimer disease-like neuropathology.  This corresponded with increased gamma-secretase activities and decreased IDE activities. Moreover, increased Abeta production also coincided with increased Alzheimer disease-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task.

 

Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor-mediated signal transduction in the brain, and perhaps more importantly an increase in glycogen synthase kinase (GSK)-3alpha.

 

As in diabetes, GSK-3 is also elevated in Alzheimer disease brain.  Furthermore, GSK-3 inhibitors prevent tau hyperphosphorylation, and also protect cultured neurons from cell death triggered by Abeta.  GSK-3 inhibition improves glucose handling in various models of insulin-resistance/diabetes prompting the development of this therapeutic class for the treatment of metabolic disorders.  This new data shows that in susceptible mice, insulin resistance can exaggerate characteristics of Alzheimer disease pathology and, furthermore, that increased GSK-3 activity may contribute to this phenomenon.  Inhibitors of GSK-3 may therefore not only be of use to  Alzheimer and metabolic disease per se but they may also break the link between the two conditions offering new treatment options to patients with metabolic disorders with or without Alzheimer disease (for a state of the art overview of GSK-3 click here).

 

(Source DailyUpdates 5th April; for a full abstract of the original papers see  FASEB J. 2004 Mar 19 [Epub ahead of print]; for further information on diabetes therapeutics and market opportunities click here; for further information on Alzheimer disease click here; and for a state of the art overview of GSK-3 click here)

 


In this edition of DailyUpdates, LeadDiscovery also highlights a role for heterodimerization of {micro} and {delta} opiate receptors in enhancing morphine analgesia...the role of CXCL12 and MMP-9 in rheumatoid arthritis...data showing that heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in myocardial infarction...and much more.

Leaddiscovery

Last updated on: 27/08/2010 11:40:18

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