A team of scientists from the Feinberg School of Medicine has taken a new approach to understanding Alzheimer’s disease.
Alzheimer’s is likely to affect more than 16 million people over the next 40 years, which makes finding effective treatment urgent, said William Thies, chief medical and scientific officer of the Alzheimer’s Association.
“We won’t be able to manage (that many Alzheimer’s patients),” he said. “To avoid this tragedy, we need better treatments and we need to find them as rapidly as possible.”
According to Prof. William Klein, senior author of the Feinberg study and researcher at Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center, the hormone insulin performs a variety of specialized functions in the brain, including the formation of memories.
Brain cells communicate with each other across small gaps known as synapses, where memories are conjured. At each synapse, brain cells reserve specific sites for insulin to attach. When the hormone binds to these insulin-only sites, the connection is made and memories are formed.
“Insulin is linked to healthy brain functioning and learning and memory,” Klein said.
Research has shown that the brain cells of Alzheimer’s patients are under siege from toxic bits of protein called amyloid beta-derived diffusible ligands, Klein said.
According to his colleagues, Klein’s research represents a novel way of dealing with the Alzheimer’s problem.
“It’s a new approach to treating Alzheimer’s disease,” said Feinberg Prof. Marsel Mesulam. “Bill’s work focused not on amyloid plaques, but on a circulating form of amyloid called ADDLs, molecules that stick to cells and hinder proper functioning.”
Scholars from other schools also applauded Klein’s approach.
“It’s a revolutionary finding by identifying a biochemical location on the synapse which connects ADDLs to (insulin) signaling processes,” said Caleb Finch, co-director of the Alzheimer Disease Research Center at the University of Southern California.
In addition to spots for insulin, synapses also reserve specific spaces for ADDLs to bind. When ADDLs bind to their own spaces, they obliterate the insulin-only binding spaces. With the insulin sites wiped out, the brain stops responding to the hormone and memory loss occurs.
In healthy brains, however, insulin signaling is strong enough that it can “fight back” and destroy ADDL binding sites, thus reducing ADDL attachment at the synapses and maintaining strong connections among brain cells.
“It’s a battle for survival at the synapses,” Klein said. “Insulin doesn’t take the hit from ADDLs without fighting back.”
But as the brain ages, the process of insulin-signaling becomes less efficient. With less insulin binding at the synapses, the brain cannot block ADDL binding as effectively and is left vulnerable to the toxins. This insulin resistance in the brain shows that Alzheimer’s may resemble a special third type of diabetes: Although insulin is being produced by the body, it cannot be properly processed by the brain, Klein said.
In the study, scientists treated brain cells from one of the brain’s memory centers with insulin and a drug used to treat type 2 diabetes. The researchers discovered that the drug boosted insulin levels, which safeguarded the brain cells by removing binding sites and prevented the toxins from attacking synapses.
The findings are being used to develop new therapeutics to combat Alzheimer’s, Klein said. The vaccine, being developed by Merck & Co. in collaboration with NU, destroys ADDLs to help bolster the positive effects of insulin.
“It’s a one-two punch against the (ADDL) toxins,” Klein said.
