A New Hope for Alzheimer's Disease: A Focus on IGF Signaling

The insulin-like growth factor (IGF) signaling pathway regulates cellular growth, survival, and metabolism. Studies have demonstrated that caloric restriction reduces IGF levels and concomitantly increases lifespan in animals. Similarly, genetic perturbation of the IGF signaling pathway increases lifespan in animal models as well. In addition, a new study published in the journal Cell suggests that a reduction in IGF signaling may lessen the severity of Alzheimer's disease.

Using an Alzheimer's disease mouse model, researchers assessed the role of reduced IGF signaling on several hallmarks of Alzheimer's disease, including memory loss and neuronal damage. IGF signaling mutants were combined with mice over-expressing a gene implicated in Alzheimer's disease that produces A-beta plaque buildup in the brain and induces an Alzheimer's like state. The effect of reducing IGF signaling in the Alzheimer's mice was assessed by behavioral assays and by measuring neuronal damage.

The effect of reducing IGF on memory in the Alzheimer's disease mouse was evaluated using a Morris water maze test. Mice were placed in a small pool of water and an escape route was learned via visual cues. Alzheimer's mice did not have a deficit in learning an escape route with this method. However, they had difficulty escaping when cues were removed and they were forced to rely on memory alone. Reducing IGF signaling in Alzheimer's mice improved their ability to find the escape route when the learned visual cues were removed. The ability of these mice to escape was similar to that of wild type controls.

The authors evaluated neuronal damage in the brains of mice carrying the A-beta plaque producing gene alone or in combination with genetically reduced IGF signaling. The authors found that the reduced IGF signaling in Alzheimer's mice was associated with a lower level of neuro-inflammation and neuronal loss. Interestingly, the mice had an equal amount of A-beta present in their brains. However, the A-beta present with IGF perturbation was assembled into a less cytotoxic form and this presumably contributed to the rescue of memory deficits and neuronal damage in Alzheimer's mice.

This study suggests a possible link between IGF signaling and Alzheimer's disease pathology. IGF signaling reduction did not reduce total A-beta levels, but did prevent neuronal damage and improved memory function. Although this work suggests a promising role for reduced IGF, and presumably caloric restriction in Alzheimer's disease, more work needs to be done to determine if IGF signaling can be therapeutically targeted to slow the progression of Alzheimer's.

References:

Cohen, E., et, al. Cell. 2009; 139; 1157-1169.

Rajpathak, SN., et, al. Diabetes Metab Res Rev. 2009; 25: 3-12.

Thorner, MO. J Gerontol A Biol Sci Med Sci. 2009; 64(10):1039-44.