Northwestern Univ. team reports in FASEB that ADDL removed insulin receptors from the surface membrane of nerve cells.

Scientists at Northwestern University believe they have found how brain insulin signaling stops working in Alzheimer’s disease. They discovered that amyloid ß-derived diffusible ligand (ADDL), found in the brains of individuals with Alzheimer’s, removes insulin receptors from nerve cells, rendering those neurons insulin resistant.

“We found the binding of ADDLs to synapses somehow prevents insulin receptors from accumulating at the synapses where they are needed,” says William L. Klein, professor of neurobiology and physiology in the Weinberg College of Arts and Sciences, who led the research team. “Instead, they are piling up where they are made, in the cell body, near the nucleus. Insulin cannot reach receptors there.”

The Northwestern team says that their current study sheds light on the emerging idea of Alzheimer’s being a type 3 diabetes. “We’re dealing with a fundamental new connection between two fields, diabetes and Alzheimer’s disease,” remarks Klein, a member of Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center. “We want to find ways to make those insulin receptors themselves resistant to the impact of ADDLs. And that might not be so difficult.”

Current clinical data suggests that ADDLs accumulate at the beginning of Alzheimer’s disease and block memory function. In earlier studies, Klein’s team found that ADDLs bind very specifically at synapses, initiating deterioration of synapse function and changing synapse composition and shape. Now they have shown that the molecules that make memories at synapses, insulin receptors, are being removed by ADDLs from the surface membrane of nerve cells.

Using mature cultures of hippocampal neurons, Klein and his team studied synapses and their insulin receptors before and after ADDLs were introduced. They report finding that the toxic protein causes a rapid and significant loss of insulin receptors from the surface of neurons, specifically on dendrites to which ADDLs are bound. ADDL binding clearly damages the trafficking of the insulin receptors, preventing them from getting to the synapses, according to the researcher.

They measured the neuronal response to insulin and found that it was greatly inhibited by ADDLs. “In addition to finding that neurons with ADDL binding showed a virtual absence of insulin receptors on their dendrites, we also found that dendrites with an abundance of insulin receptors showed no ADDL binding,” notes co-author Fernanda G. De Felice, a visiting scientist from Federal University of Rio de Janeiro. “These factors suggest that insulin resistance in the brains of those with Alzheimer’s is a response to ADDLs.”

According to Klein, “With proper research and development the drug arsenal for type 2 diabetes, in which individuals become insulin resistant, may be translated to Alzheimer’s treatment. I think such drugs could supercede currently available Alzheimer’s drugs.”

The study is published online by The FASEB Journal.

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