In November, researchers reported that the drug lecanemab slowed the progression of Alzheimer’s disease. The effect was modest, but it generated enormous excitement as it was the first time that a drug was able to influence the course of this incurable and relentless disease.
The drug, lecanemab, is an antibody made that helps break down an abnormal protein called beta-amyloid, which forms insoluble clumps called amyloid plaques around brain cells. Amyloid is thought to initiate and sustain the destruction of brain cells that leads to the cognitive decline and eventual dementia that afflicts patients with Alzheimer’s disease.
But many researchers believe that for a treatment to have a major impact on the course of Alzheimer’s disease, it will also have to target a second protein which, to date, has not received as much attention as the beta-amyloid, a protein called tau.
Amyloid plaques trigger the disease cascade, so it makes sense to try to clear them, but it’s the tau that kills the cells. »
Brian Kraemer, Professor of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine
Kraemer specializes in neurodegenerative diseases caused by tau, called tauopathies. These include a long list of incurable neurodegenerative diseases. In some, abnormal tau seems to be the primary cause of the disorder. We then speak of pure tauopathies. They include frontotemporal lobar degeneration, progressive supranuclear palsy, and Pick’s disease. On the other hand, Alzheimer’s disease is called a mixed tauopathy because beta-amyloid plays a role.
Tau, which rhymes with “wow,” stabilizes crucial structures within cells called microtubules. These structures serve as the internal skeleton of a cell and act as conduits through which the cell transports material from one place to another.
In Alzheimer’s disease and other tauopathies, tau is defective. It detaches from microtubules and forms cell-insoluble aggregates called neurofibrillary tangles. The breakdown of microtubules and the accumulation of neurofibrillary tangles disrupt the ability of brain cells to function and ultimately lead to cell death.
“If we were to target one thing in Alzheimer’s disease, we would probably target tau,” Kraemer said. “It is most closely related to the decline of cognitive dysfunction. You want to get rid of the amyloid, but what you really want is the preservation of cognition. This requires targeting tau. »
In a paper published in the journal Proceedings of the National Academy of Sciences on Dec. 26, Kraemer, his team and lead author Randall Eck, a student in UW’s neuroscience graduate program, report the identification of ‘a protein that appears to be crucial in the formation of abnormal collections of tau. Scientists have shown that by blocking the gene necessary for the production of the protein, it is possible to prevent the accumulation of tau in an animal model.
The protein is called speckle-like POZ protein (SPOP). The name refers to how it is found in the spot-like compartments in the cell and the fact that it contains a particular stretch of amino acids known as the POZ domain. It’s one of several proteins that Kraemer and his colleagues have linked to tauopathies. Another protein, called SUT-2 for tauopathy suppressor-2, is being explored for its therapeutic potential.
The exact role the protein plays in diseases involving tau is unclear. But it appears to be involved in an essential process by which cells manipulate and eliminate faulty proteins. The results suggest that if drugs that inhibit the effect of this protein could be developed, it might be possible to treat Alzheimer’s disease and other tauopathies.
To identify these key regulatory proteins, Kraemer and his colleagues use an animal model created by his lab two decades ago. The model is a genetically modified version of a small worm, normally found in soil, called Caenorhabditis elegansor C. elegans to shorten it. C. elegans only lives for about three weeks, so it’s ideal for studying how genetic mutations affect an organism’s growth, development, and functioning throughout its lifespan.
To create the model, Kraemer and his team introduced the human tau gene into roundworms.
In their experiments, the scientists demonstrated that the altered worms develop many of the abnormalities seen in human tauopathies: accumulation of insoluble tau, progressive nerve cell death, behavioral deficits and shortened lifespan.
The researchers then screened all of the worm’s genes to see if randomly knocking out one of them could prevent these changes. This approach led them to first identify the SUT-2 gene and more recently SPOP.
“When we eliminate the SPOP protein in our tau worm model, we see a dramatic decrease in tau accumulation and progressive nerve cell death as well as an improvement in behavioral deficits and lifespan,” said Eck said.
Kraemer, Eck and other researchers in the field are now investigating whether their findings in this C. elegans model can be translated into treatments in humans. The first step is to see if deleting these genes can have a similar protective effect in a mouse model of the disease. Studies deleting the SUT-2 gene are promising and studies on SPOP are ongoing.
“We are still in the early days of developing effective drugs for Alzheimer’s disease,” Kraemer said. “A tau inhibitor may be enough to treat pure tauopathies, but for Alzheimer’s disease, I think we’re going to have to hit both tau and amyloid to have an effective treatment. »