Insulin May Become a New Treatment for Alzheimer's

(Isolated hippocampal cells are used by scientists to study memory chemistry; the cells are susceptible to damage caused by amyloid beta-derived diffusible ligands [ADDLs], toxic proteins that build up in individuals with Alzheimer's disease.)

The researchers, from Northwestern University (Evanston, IL, USA), discovered that injury to neurons exposed to ADDLs was blocked by insulin, which kept ADDLs from attaching to the cells. They also found that protection by low levels of insulin was enhanced by rosiglitazone. ADDLs were discovered at Northwestern and are known to attack memory-forming synapses. After ADDL binding, synapses lose their capacity to respond to incoming information, resulting in memory loss.

The protective process of insulin works through a series of stages by ultimately reducing the actual number of ADDL-binding sites, which then results in a marked reduction of ADDL attachment to synapses, the researchers reported. "Therapeutics designed to increase insulin sensitivity in the brain could provide new avenues for treating Alzheimer's disease,” said senior author William L. Klein, a professor of neurobiology and physiology in the Weinberg College of Arts and Sciences and a researcher in Northwestern's Cognitive Neurology and Alzheimer's Disease Center. "Sensitivity to insulin can decline with aging, which presents a novel risk factor for Alzheimer's disease. Our results demonstrate that bolstering insulin signaling can protect neurons from harm.”

The amyloid beta oligomers, or ADDLs, form when pieces of a protein clump together in the brain. In Alzheimer's disease, when ADDLs bind to neighboring neurons, they cause damage from free radicals and a loss of neuronal structures critical to brain function, including insulin receptors. This damage ultimately results in memory loss and other Alzheimer's disease symptoms. The Alzheimer's drug Namenda has been shown to partially protect neurons against the effects of ADDLs.

"The discovery that anti-diabetic drugs shield synapses against ADDLs offers new hope for fighting memory loss in Alzheimer's disease,” said lead author Dr. Fernanda G. De Felice, a former visiting scientist in Klein's lab and an associate professor at the Federal University of Rio de Janeiro (Brazil).

"Recognizing that Alzheimer's disease is a type of brain diabetes points the way to novel discoveries that may finally result in disease-modifying treatments for this devastating disease,” added Dr. Sergio T. Ferreira, another member of the research team and a professor of biochemistry at the Federal University of Rio de Janeiro.

In other recent and related research, Drs. Klein, De Felice, and their colleagues demonstrated that ADDLs bound to synapses remove insulin receptors from nerve cells, rendering those neurons insulin resistant. The outcome of the molecular-level battle between ADDLs and insulin, which in the current study was found to remove ADDL receptors, may determine whether an individual develops Alzheimer's disease.

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