Alzheimer’s disease is a neurodegenerative disease that affects tens of millions of people worldwide today. It is characterized by two lesions: amyloid deposits and tangles of tau protein. Several treatments have been developed in recent years, targeting one or other of these lesions in order to delay the progression of the disease. But recently, researchers have identified a crucial mechanism of the disease: the process by which beta-amyloid causes tau tangles. A discovery that could lead to treatments far more effective than current therapies.
Alzheimer’s disease has long been characterized by the accumulation of two separate proteins in the brain: first beta-amyloid, which builds up in plaques, then tau, which forms toxic tangles that lead to cell death. . But the way in which beta-amyloid leads to the toxicity of the tau protein has never been precisely known. Now, a new study at the University of Alabama in Birmingham seems to describe this missing mechanism.
Published in the journal Science Translational Medicine, the study details a cascade of events. The accumulation of beta-amyloid activates a receptor that responds to a chemical signal from the brain called norepinephrine, commonly known to mobilize the brain and body for action. Activation of this receptor by both beta-amyloid and norepinephrine stimulates the activity of an enzyme that activates the tau protein and increases the vulnerability of brain cells.
The role of norepinephrine in the virulence of Alzheimer’s disease
Essentially, beta-amyloid bypasses the norepinephrine pathway to trigger a toxic build-up of tau, says Qin Wang, a neuropharmacology researcher in the Department of Cell, Developmental and Integrative Biology at the University of Alabama in Birmingham. ” We really show that this norepinephrine is a missing piece of the whole Alzheimer’s puzzle “.
This cascade explains why so many previous treatments for Alzheimer’s disease have failed. Most of the drugs developed in recent decades have targeted the elimination of beta-amyloids. But new research suggests that norepinephrine amplifies the damage caused by this protein. Beta-amyloid itself can kill neurons, but only in very high doses.
Alzheimer’s disease is characterized by two types of lesions: the amyloid plaques between the neurons and the tau neurofibrilar lesions (tangles) inside the neurons. For a long time, the link between beta-amyloid and tau has escaped biologists. But Wang’s team has shown that norepinephrine plays the main role in this process. Credits: Dr Holland
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Add norepinephrine and only 1-2% beta-amyloid is needed to kill brain cells in a laboratory dish. So with treatments that targeted beta-amyloid but left the norepinephrine pathway intact, there was enough beta-amyloid left to do significant damage. But if the norepinephrine pathway is really crucial for the development of Alzheimer’s disease, it suggests new ways to treat the disease.
Towards the development of a drug targeting the norepinephrine pathway
A drug that was developed to treat depression, but too ineffective to be approved, seems to work in this same direction. The drug, idazoxan, which has also been studied in schizophrenia, has already undergone the first clinical tests and has been shown to be safe. Wang is now looking to promote larger clinical trials of idazoxan to see if it can be used to effectively treat Alzheimer’s disease at an early stage.
She hopes that in the long term, a drug which will act on this path linked to Alzheimer’s disease in a more targeted way can be developed, in order to minimize the side effects and maximize the effectiveness. Stephen Salloway, professor of psychiatry and neurology at the Warren Alpert Medical School at Brown University, says he doesn’t think Alzheimer’s will give in so easily to a new drug targeting the norepinephrine pathway.
” I doubt there’s anything simple that will come out. I would be shocked if it works “. Such a drug, however, could be part of a “therapeutic package” of treatments that could potentially advance Alzheimer’s disease, he said. ” The goal is to gain a foothold on the biological level, then to develop it. The more objectives we have, the greater the impact “.
The binding of beta-amyloid to norepinephrine would be responsible for the toxicity of the tau protein
Wang has a long history of norepinephrine because of its role in complex thinking and behavior. She came across the link with Alzheimer as part of this research. In two strains of mice and in human tissue in their new study, she and her colleagues showed that small pieces of beta-amyloid bind to a norepinephrine receptor, activating the enzyme GSK3-beta and causing the toxicity of tau.
Graphs and microscopic images showing the efficacy of idazoxan (inhibitor of the enzyme GSK3-beta) on the activity of beta-amyloid; it is blocked and cannot bind to norepinephrine, greatly reducing the toxicity of the tau protein. Credits: Fang Zhang et al. 2020
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On the same subject: Alzheimer’s disease: an alternative mechanism could explain its appearance
They confirmed this relationship by blocking the receptor with idazoxan in two strains of middle-aged mice for eight weeks. This deactivated the enzyme and prevented tau from becoming toxic. For years, researchers have wondered how beta-amyloids and tau are linked, says Rudolph Tanzi, an expert in molecular genetics of Alzheimer’s disease at Massachusetts General Hospital.
Scientists have essentially assumed that beta-amyloid has caused tau tangles through a complicated chain of events. Then, in an article published in 2014 in Nature, Tanzi and colleagues used cultured human brain cells to reveal a problem with theory: mice – the main source of Alzheimer’s research information – don’t have the right form of tau entanglement in humans.
Block the GSk3-beta enzyme to neutralize inflammation
Instead, researchers have shown that in human cells, beta-amyloid directly causes tangles of tau. Tanzi and his colleagues blocked a variety of different enzymes called kinases in an attempt to stop the process. They found two, both of which blocked the GSK3-beta enzyme – the same one that Wang and his colleagues identified in their research.
In 2014, Wang and his team had already shown that 1-Azakenpaullone, an inhibitor of the enzyme GSK3-beta, neutralized the formation of beta-amyloid responsible for the induction of tau toxicity (in yellow). Credits: R. Tanzi et al. 2014
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Tanzi believes that inflammation is a key player in Alzheimer’s disease, triggering the cascade that leads to the disease. He previously described beta-amyloid as the match and tangles of tau as brushwood that catches fire. Tanzi says he has unpublished data on dozens of drugs that stop beta-amyloid from triggering tangles, many of which support what Wang and his colleagues found in their new document.
Sources: Science Translational Medicine
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