A new approach to a deadly disease

"When I was in graduate school, three articles a month were published on Alzheimer's disease. Now, there are thousands each month.

Neurobiology professor Bill Klein explains that the understanding of Alzheimer's has been revolutionary over the last 20 years. This radical change, he says, focused on two major Alzheimer's brain abnormalities: amyloid plaques and tau protein entanglements.

"Alzheimer's has been defined as dementia with plaques and tangles," says Klein. Dementia is a broad term and Alzheimer's disease is the most prevalent form among people over 65 years old. Determined to improve diagnostic tools and develop more effective treatments, Klein has spent decades looking beyond plaques and entanglements for drivers of the disease.

Tiny toxins in the brain

Early in his career, Klein was focused on amyloid plaques, but an unexpected discovery led him to a very different path. With his colleagues, he first of all badumed that if they could stop the growth of these amyloid plaques, they could prevent Alzheimer's disease from damaging the cell tissue. But even after successfully stopping plaque growth, the damage continued, prompting researchers to examine the brain before plaque formation. It is thanks to these works that they identified the Abeta oligomers, which would become the center of Klein's research.

In a healthy brain, the Abeta molecule is created and eliminated at an equal rate, like the brain that regularly pulls out garbage. But if the brain does not suppress Abeta enough, the molecules form tiny clusters – the Abeta oligomers. These accumulate in the Alzheimer's brain, like a toxic mold that accumulates in your home.

In a 1998 article, Klein's team showed that Abeta oligomers attach to nerve synapses, where they prevent 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 nodes in tau proteins.

"First, there is an effect on the signaling, and then the synapse gets worse," says Klein. "In the end, the whole neuron is deteriorating."

Following Klein's discovery, Eliezer Masliah, director of neuroscience at the National Institute of Aging, said that "the progressive accumulation of Abeta oligomers has been identified as one of the major toxic effects of Alzheimer's disease. ".

Abeta oligomers attach to nerve synapses, blocking signals in the brain and disrupting the process of memory formation

Bucking Convention

Despite Masliah's proclamation, Klein says he is swimming upstream. Indeed, many people still consider amyloid plaques – not Abeta oligomers – as the hallmark of Alzheimer's disease. But according to Klein, evidence suggests that the presence of plaques does not mean that a person has Alzheimer's disease and that the disease can occur without any plaque.

"We worked with a team of scientists in Japan who identified a family in the city of Osaka who contract Alzheimer's disease because she is carrying a mutation – the so-called Osaka mutation," says Klein. "They have all the pathology of Alzheimer's disease and they make a lot of oligomers, but they do not 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. "The amyloid was ineffective, but the oligomers were incredibly powerful at inhibiting the mechanism of memory," says Klein. "It was a very exciting result, which caused many pathologists to stay away from this theory of amyloid."

A diagnostic test

Klein's team has developed MRI tools to identify oligomers in the Alzheimer's brain. She is now working with Northwestern Urology Professor Shad Thaxton to develop clinical tools to detect toxins in blood plasma and cerebrospinal fluid. This collaboration builds on Klein's earlier work with chemistry teachers Chad Mirkin and Rick van Duyne, who showed that people with Alzheimer's disease in cerebrospinal fluid had high levels of oligomers, while that people without Alzheimer's disease had low levels of oligomers.

Klein's laboratory has a general purpose – to develop a molecular basis for the cause, diagnosis, and treatment of Alzheimer's disease – and their work bears witness to this.

"We have a lot of projects going on," says Klein. "We want to create a blood test to detect oligomers. We also continue to consider spinal fluid – and now – brain imaging as an approach for non-invasive studies. "

A hope (of treatment) for the future

At least three companies are currently testing treatments for Abeta oligomers. One of these companies, Acumen Pharmaceuticals, co-founded by Klein in the 1970s, is testing an antibody vaccine approved by Northwestern. This antibody binds to oligomers and renders them incapable of damaging nerve signaling.

According to Klein, the anti-antibody vaccine works as an anti-venom treatment after a rattlesnake bite. In the same way that the anti-venom drug neutralizes the toxin in the bite, the antibody neutralizes the oligomers in the brain.

Klein hopes that the Acumen vaccine – and perhaps other treatments – will be available in less than a decade.

"Some people think that an effective treatment could be available by 2025," he says. "I do not think it's so crazy."

William Klein

William Klein is Professor of Neurobiology at the Faculty of Arts and Sciences at Weinberg and Professor of Neurology at the Feinberg School of Medicine. He is a member of the Mesulam Center for Cognitive Neurology and Alzheimer's Disease of the North West, Center for Molecular Innovation and Drug Discovery (CMIDD), Institute of Chemistry of Life Processes (CLP) and the International Institute for Nanotechnology (IIN).

Journalists: See Bill Klein's press material here.