“When I was in graduate school, three papers per month were published on Alzheimer’s disease. Now, there are thousands every month.”
Neurobiology professor Bill Klein says the last 20 years have seen a revolution in the understanding of Alzheimer’s disease. That sea change, he says, has been focused on two key abnormalities in the Alzheimer’s brain: amyloid plaques and tau protein tangles.
“Alzheimer’s has been defined as dementia with plaques and tangles,” Klein says. Dementia is a broad term, and Alzheimer’s disease is the most common form among people over age 65. Determined to both improve diagnostic tools and develop more effective treatments, Klein has spent decades looking beyond plaques and tangles toward the tiny toxins he says are the true drivers of the disease.
Tiny toxins in the brain
Early in his career, Klein was focused on amyloid plaques, but a surprise finding led him down a vastly different path. He and his colleagues initially assumed that if they could halt the growth of these amyloid plaques, they could stop Alzheimer’s from damaging cell tissue. But even after they successfully stopped plaque growth, the damage continued, prompting the researchers to look at the brain before plaque formation. It was through this work that they identified Abeta oligomers, which would become the central focus of Klein’s research.
In a healthy brain, the molecule Abeta is created and cleared at an equal rate, like the brain regularly taking out the trash. But if the brain does not clear Abeta sufficiently, the molecules form tiny clusters — Abeta oligomers. These build up in the Alzheimer’s brain — like toxic mold building up in your home.
In a breakthrough 1998 paper, Klein’s team showed that Abeta oligomers attach to nerve synapses, where they impede signaling and destroy the delicate system that forms new memories. These oligomers cause changes in the nerve cell that eventually lead to the formation of tau protein tangles.
“First, there’s the effect on signaling, and then there’s a deterioration of the synapse,” Klein says. “Ultimately, the entire neuron deteriorates.”
Following Klein’s discovery, Eliezer Masliah, director of neuroscience at the National Institute on Aging, said that “progressive accumulation of Abeta oligomers has been identified as one of the central toxic events in Alzheimer’s disease.”
Abeta oligomers attach to nerve synapses, blocking signals in the brain and disrupting the process of memory formation
Despite Masliah’s proclamation, Klein says he’s swimming upstream, in that amyloid plaques — not Abeta oligomers — are still regarded by many as the hallmark of Alzheimer’s. But Klein says there is evidence to suggest the presence of plaques does not mean a person has Alzheimer’s, and the disease can occur without any plaques at all.
“We’ve worked with a team of scientists in Japan who have identified a family in the city of Osaka who develops Alzheimer’s disease because they have a mutation — the so-called Osaka mutation,” Klein says. “They get all of the pathology of Alzheimer’s disease, and they make lots of oligomers, but they don’t make plaques.”
In a related experiment, Klein’s team injected amyloid into the brains of some mice, and Abeta oligomers into the brains of others. “Amyloid was without effect, but the oligomers were incredibly potent at inhibiting the memory mechanism,” Klein says. “That was a very exciting result, and it caused a lot of pathologists to say ‘hold on’ with this amyloid theory.”
A diagnostic test
Klein’s team has developed MRI tools to identify oligomers in the Alzheimer’s brain, and Klein is now working with Northwestern urology professor Shad Thaxton to develop clinical tools to detect the toxins in blood plasma and spinal fluid. This collaboration builds on Klein’s earlier work with chemistry professors Chad Mirkin and Rick van Duyne, which showed people with Alzheimer’s disease in their spinal fluid had high levels of oligomers, while people who did not have Alzheimer’s disease had low levels of oligomers.
Klein’s lab has a broad goal — to develop a molecular basis for the cause, diagnosis and treatment of Alzheimer’s disease — and their work reflects that breadth.
“We have our fingers in lots of projects,” Klein says. “We would like to create a blood test to detect oligomers. We also continue to look at spinal fluid — and now — brain imaging as an approach for non-invasive studies.”
A (treatment) hope for the future
At least three companies are now testing therapeutics aimed at Abeta oligomers. One of these companies — Acumen Pharmaceuticals, which Klein co-founded in the 1970s, is testing an antibody vaccine licensed from Northwestern. This antibody binds to oligomers and renders them unable to damage nerve signaling.
Klein says the antibody vaccine works like an anti-venom treatment after a rattlesnake bite. In the same way the anti-venom drug neutralizes the toxin in the bite, the antibody neutralizes the oligomers in the brain.
Klein is hopeful that Acumen’s vaccine — and maybe other treatments — will be available in under a decade.
“Some people think an effective therapeutic could be out there by 2025,” he says. “I’m not thinking that that’s so crazy.”