Alzheimer's disease: a crucial mechanism in the fight against the disease has been identified

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.

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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. . However, 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 which responds to a chemical signal from the brain called noradrenaline, commonly known to mobilize the brain and the 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. Biologists have long missed the link between beta-amyloid and tau. But Wang's team has shown that norepinephrine plays the main role in this process. Credits: Dr Holland

Add norepinephrine and only 1-2% beta-amyloid is needed to kill brain cells in a laboratory can. 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 of treating 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 manner can be developed, in order to minimize the side effects and maximize the effectiveness. Stephen Salloway, professor of psychiatry and neurology at Warren Alpert Medical School at Brown University, says he doesn't think Alzheimer will give in so easily to a new drug targeting the norepinephrine pathway.



“I doubt there is anything simple that will come out of it. 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 goals 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

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 basically assumed that beta-amyloid had caused tau tangles through a complicated chain of events. Then in a 2014 article in Nature , Tanzi and colleagues used cultured human brain cells to reveal a problem with the theory: mice - the main source of research information on Alzheimer's disease - do not have the right form of tau which becomes entangled 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 to try 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 GSK3-beta enzyme, neutralizes the formation of beta-amyloid responsible for the induction of tau toxicity (in yellow). Credits: R. Tanzi et al. 2014

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 prevent beta-amyloid from triggering tangles, many of which support what Wang and his colleagues found in their new document.

Bibliography: β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade Fang Zhang, Mary Gannon, Yunjia Chen, Shun Yan, Sixue Zhang3, Wendy Feng1, Jiahui Tao1, Bingdong Sha, Zhenghui Liu, Takashi Saito, Takaomi Saido, C. Dirk Keene, Kai Jiao, Erik D. Roberson, Huaxi Xu and Qin Wang Science Translational Medicine  15 Jan 2020: Vol. 12, Issue 526, eaay6931 DOI: 10.1126/scitranslmed.aay6931