Alzheimer's new drug controversial listing, can the new target discovered by Yu Shanping's team bring new hope?

"Alzheimer's research has always been dominated by theory
.

The'invalid' new drug that the US FDA has just approved will further mislead Alzheimer's research.
I don't want to be misled in the country and provide a new perspective to people of insight.
", said Yu Shanping, now a tenured professor at Emory University in the United States
.

Recently, Yu Shanping’s team revealed a new mechanism that causes Alzheimer’s syndrome, which may bring a ray of life to the difficult Alzheimer’s drug development
.

Yu Shanping, a tenured professor of Emory University in the United States, graduated from the Capital Medical University in Shanping in his early years.
In the 1990s, he went to the United States to obtain a Ph.
D.
from the State University of New York at Stony Brook
.

Later, he worked as a postdoctoral fellow at the Howard Hughes Institute of Medical Research in the United States, and then served as an assistant professor and associate professor of neurology at the University of Washington in the United States.
He is now the titled chair professor of the Department of Anesthesiology at Emory University in the United States
.

In his early years, Yu Shanping was mainly engaged in the study of ion channel changes and protective mechanisms of cell death during stroke.
In recent years, his research has expanded to brain trauma and degenerative neurological diseases, such as Alzheimer's syndrome
.

Anti-Alzheimer's drug is marketed amidst controversy.
In June 2021, the US Food and Drug Administration (FDA) approved the pharmaceutical company Biogen's anti-Alzheimer's drug Aducanumab (aducanumab) to be marketed, despite nearly 20 No new drugs were approved in the Alzheimer's field in 2016, but when the news came out, it was quite controversial, and it did not bring excitement to the public but general worries
.

Because, the previous clinical trials of Aducanumab against Alzheimer were not good and did not reach the effective clinical endpoint.
In this case, the US FDA still ignored the objections of the external expert group and approved Aducanumab Many experts who participated in the review even resigned to protest
.

Since then, the US FDA stated in response to the media, “The FDA requires Biogen to conduct a new randomized, controlled clinical trial to verify the clinical benefit of the drug
.

If the trial fails to verify the clinical benefit, the FDA may initiate a procedure to withdraw the treatment.
Approval of the drug
.

” This means that Aducanumab is conditionally approved for marketing this time
.

In fact, Aducanumab is not original by Biogen, but it was introduced from Neurimmune and jointly developed.
It is a humanized monoclonal antibody that was jointly developed by Biogen and Japanese pharmaceutical company Eisai in 2017
.

The basic principle of Aducanumab is to eliminate the β-amyloid protein in the brain as the goal, and then achieve the purpose of treating Alzheimer's syndrome
.

Beta-amyloid protein is also known as "toxin protein.
" Previous studies have shown that the accumulation of this toxin protein in the brains of Alzheimer's patients can disrupt the function of normal neurons, thereby affecting the function of the entire brain
.

In addition to β-amyloid, there is also a protein called tau, which replicates abnormally in the brain and can also cause neuronal damage
.

However, the current failure rate of drugs targeting β-amyloid and tau protein is as high as 99%.
Basically, β-amyloid is cleared but the cognitive function of the brain has not changed.
At the same time, clinical data shows that β- in human brain tissue There is no direct correlation between amyloid levels and cognitive function
.

"Based on this, some researchers have begun to question whether β-amyloid protein precipitation is really a causative factor of Alzheimer's disease, and have successively put forward some other hypotheses, such as the inflammation hypothesis, the choline hypothesis, the mitochondrial metabolism hypothesis, and oxygen free radicals.
Hypothesis and so on"
.

Yu Shanping explained
.

But almost all of these hypotheses are based on changes in β-amyloid
.

This situation is largely constrained by Alzheimer's disease research that relies heavily on a transgenic mouse model of β-amyloid protein
.

This model of Alzheimer's disease created by foreign gene expression does not seem to represent the vast majority of secondary Alzheimer's disease in the clinic
.

"Workers must first sharpen their tools if they want to do their jobs well.
" The breakthrough in Alzheimer's disease research suffers from the lack of theories and related animal models for the initial mechanism of the disease
.

Revealing the initial pathogenesis and prevention targets of Alzheimer's disease Yu Shanping and his team have been engaged in the study of nerve cell damage, especially for the acute and chronic nerve damage mechanisms after stroke
.

Yu Shanping noticed that during the development of Alzheimer's disease, the NMDA receptor, an important receptor of excitatory neurons, exhibits high activity, which triggers a disorder in the regulation of intracellular calcium ion concentration
.

This calcium imbalance has the same mechanism as acute nerve injury after stroke, but it also has the characteristics of small and long-lasting changes
.

Alzheimer’s syndrome mediated by long-term calcium imbalance Yu Shanping’s team found that in mice with the NMDA receptor inhibitory subunit GluN3A knocked out, the deletion of the GluN3A subunit is a key regulatory protein that causes long-term calcium imbalance
.

Without the need for artificial expression of exogenous genes, GluN3A knock-out mice will age with age, and will first experience the deterioration of olfactory function that many early Alzheimer patients have, accompanied by the structure and function of brain nerve synapses.
Defects, decreased nerve cells, and then the typical symptoms of Alzheimer's disease such as decreased learning and memory abilities
.

Surprisingly, during the occurrence of these structural and functional degenerative diseases, there is no significant deposition of β-amyloid protein
.

In GluN3A-deficient mice, endogenous β-amyloid deposition and tau hyperphosphorylation occurred after the degenerative disease rather than before, suggesting that they are the result of Alzheimer's disease rather than the cause
.

This important discovery reveals a new target for the pathogenesis and early treatment of Alzheimer's disease that does not depend on changes in β-amyloid protein
.

Related research is published as a Featured Article in Alzheimer's and Dementia, an authoritative journal in the field of Alzheimer's syndrome and dementia research
.

The journal is also the journal of the Alzheimer Society of America
.

Yu Shanping pointed out, “GluN3A, the inhibitory subunit of the NMDA receptor, is very unique.
Its endogenous inhibitory regulation is not found in other membrane receptors, and it only appeared in the vertebrate stage during biological evolution.
This suggests that it It is born to adapt to higher-level neural regulation, including cognitive level and many other functions, and the current status of research on Alzheimer's disease
.
"
As for what else will they do for this target in the future? Yu Shanping said that they will advance both basic molecular biology and clinical translation for this target and related mechanisms
.

There is a lot of work that can be done in the areas of protein and genomics, receptor regulation, and drug intervention
.

Link to the paper: https://alz-journals.
onlinelibrary.
wiley.
com/doi/10.
1002/alz.
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