A promising new target for the treatment of Alzheimer’s disease and related dementia

The cytotoxic tau isomer (cis P-tau; red) partially coexists with tau oligomers (green, top) and tau tangles (green, bottom) in Alzheimer’s disease (AD) and mixed brains of AD and VCID. Localized, but detected in the absence. VCID of other tau isoforms in the brain. Credits: Image provided by Dr. Onder Albayram, South Carolina Medical College.

Researchers are still puzzled about the causes of dementia and how to treat and remedy the cognitive decline seen in patients. Researchers at the South Carolina Medical College (MUSC) and Harvard Medical School’s Beth Israel Deaconess Medical Center (BIDMC) have discovered a toxic, non-degradable version of cis P-tau in an unprecedented study. did. It is a healthy brain protein and an early marker for vascular dementia (VaD) and Alzheimer’s disease (AD). The results were published on June 2nd. Science translational medicine, Defines the molecular mechanism that causes the accumulation of this toxic protein. In addition, we have shown that monoclonal antibodies (mAbs) that target this toxic protein can prevent disease pathology and amnesia in preclinical models such as AD and VaD. In addition, this treatment could even reverse cognitive impairment in preclinical models such as AD.

“Our discovery not only discovered cis P-tau as an early major driver of previously unrecognized VaD and AD, but also this general for early treatment and prevention of AD and VaD. We are confident that highly effective and specific immunotherapies targeting drivers of specific diseases have also been identified, said Dr. Onder Albayram, co-chief author and assistant professor of the Department of Cardiology, MUSC School of Medicine. I will.

Aging is a normal part of life, weakening bones and muscles, stiffening blood vessels, and impairing memory. However, for about 50 million people worldwide, these memory deficits become increasingly severe and ultimately lead to the diagnosis of dementia.

Dementia is a comprehensive term that covers AD, accounting for 60% to 80% of cases. VaD, the second most common cause. And other less common medical conditions. Currently, there is no effective treatment for AD. Interestingly, most AD cases have vascular components, suggesting a broader relationship between cognitive function and a healthy cerebrovascular system. A better understanding of the relationship may provide a platform for discovering new therapeutic targets.

“Our study provides evidence that cis P-tau may be the virulence factor that explains VaD. VaD is generally not associated with other dementia.” Added, Dr. Chenxi Qiu, BIDMC Co-Principal Investigator and Postdoctoral Fellow. Harvard Medical School.

In a preclinical model of VaD, young mice show signs of brain inflammation, amnesia Within 1 month. However, treatment of these mice with cis P-tau mAb prevented nerve deterioration and cognitive decline for up to 6 months. In another preclinical model of AD, older mice showed severe cognitive impairment. Interestingly, administration of cis P-tau mAb to mice significantly improved this serious disorder.

“These data show that cis P-tau may be an early upstream virulence factor common to both diseases,” said Albayram.

Translation of information obtained from Preclinical model Often difficult for humans, this study provides a reason for optimism. In the VaD model, the accumulation of cis P-tau dramatically changed the genetic structure of the affected cells. These changes were consistent with those seen in human AD patients. Researchers have also shown that treatment with cis P-tau mAb reversed 85% to 90% of these changes, suggesting this potential therapeutic power.

“After silencing this toxic protein, the genomic landscape really adapts,” Albairam said. “It was a big discovery.”

Not only are Albayram and Qiu excited about these discoveries, but MUSC colleagues are already very enthusiastic about this study.

“I can talk about this treatise as many times as I want,” said Adviye Ergul, MD, Ph.D., a professor of pathology and laboratory medicine at MUSC School of Medicine. “They provide solid evidence that there is an accumulation of a particular form of tau protein-cis P-tau-that highlights the pathology of different tau proteins in VaD studies.”

This groundbreaking study opens the door to new immunotherapeutic possibilities and highlights several new areas of research that need to be investigated. Researchers have drawn pathways leading to the accumulation of cis P-tau, but the underlying link between vascular abnormalities and pathway activation needs to be identified. A better understanding of how toxic cis P-tau interacts with healthy trans P-tau may provide further insight into the progression of AD disease.

AD and VaD may not be the only illnesses affected by high levels of cis P-tau. Other brain disorders with vascular components may also result from this toxic protein, but further research is needed to establish such a link.

“Cis P-tau can be a common early virulence factor underlying traumatic brain injury, VaD and AD,” said Qiu.

As we grow older and lose our car keys or forget the names of new acquaintances, we fear that these may be the first signs of dementia. Currently, there is no approved treatment to reverse the physiological effects of dementia, but this new study may bring hope that a new treatment is imminent.

Women Accumulate Alzheimer’s Related Proteins Faster

For more information:
Chenxi Qiu et al., Cis P-tau, underlies vascular contributions to cognitive impairment and dementia and can be effectively targeted by mouse immunotherapy. Science translational medicine (2021). DOI: 10.1126 / scitranslmed.aaz7615

Quote: Don’t forget: A promising new target for the treatment of Alzheimer’s disease and related dementia (10 June 2021), 10 June 2021 Obtained from alzheimer-dementias.html

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A promising new target for the treatment of Alzheimer’s disease and related dementia

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