A new goal is promising in the treatment of Alzheimer’s and related dementias

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

Researchers remain perplexed about what causes dementia and how to treat and reverse the cognitive impairment observed in patients. In a first study of this type, researchers at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School found that cis P-tau, a toxic and non-degradable version of a healthy brain protein, is an early marker of vascular dementia (VaD) and Alzheimer’s disease (AD). Their results, published on June 2 a Scientific translational medicine, defines the molecular mechanism that causes an accumulation of this toxic protein. In addition, they demonstrated that a monoclonal antibody (mAb) targeted to this toxic protein was able to prevent disease pathology and memory loss in preclinical models similar to AD and VaD. In addition, this treatment was even able to reverse cognitive impairment in a preclinical model similar to AD.

“We believe that our findings have not only discovered cis P-tau as a major early promoter of VaD and antidiabetic disease, but have also identified highly effective and specific immunotherapy to address this common disease factor. to treat and prevent disease and VaD in the early stages, ”said Onder Albayram, Ph.D., co-lead author and assistant professor in the Cardiology Division of the MUSC Department of Medicine.

Aging is a normal part of life: we experience a weakening of bones and muscles, a hardening of blood vessels and some memory deficiencies. But for nearly 50 million people worldwide, these memory deficiencies become progressively more severe and ultimately lead to a diagnosis of dementia.

Dementia is a general term that covers AD, which accounts for between 60% and 80% of cases; VaD, the second most common cause; and other less common pathologies. There are currently no effective treatments for AD. Interestingly, most cases of AD have a vascular component, suggesting a broader relationship between cognitive function and healthy cerebral vasculature. A better understanding of this relationship could provide a platform for discovering new therapeutic targets.

“Our work provides evidence that cis P-tau may be a pathogenic factor that explains VaD, which is generally unrelated to other dementias,” added Chenxi Qiu, Ph.D., co-lead author and postdoctoral researcher at BIDMC, Harvard Medical School.

In a preclinical model of VaD, young mice showed signs of cerebral inflammation and in a month. However, treating these mice with cis P-tau mAb prevented neuronal degradation and cognitive impairment up to six months. In a separate preclinical model of AD, old mice showed severe cognitive impairment. Excitingly, this severe deterioration was significantly reversed when the cis P-tau mAb was administered to the mice.

“These data show that cis P-tau could be an early up pathogen common to both diseases,” Albayram said.

Translate the information obtained from for humans it is often difficult, but this study offers reasons to be optimistic. Cis P-tau accumulation caused dramatic changes in the genetic architecture of affected cells in a VaD model; These changes were consistent with those observed in patients with human AD. The researchers showed that cis P-tau mAb treatment reversed between 85% and 90% of these changes suggesting the power of this potential therapy.

“The genomic landscape really adapts after silencing this toxic protein,” Albayram said. “It was a great discovery.”

Albayram and Qiu are not only excited about these findings, but their MUSC colleagues are already very excited about this work.

“I can continue to follow this article,” said Adviye Ergul, MD, Ph.D., a professor in the College of Medicine, Department of Pathology and Laboratory Medicine at MUSC. “They provide robust evidence that there is accumulation of a specific form of tau protein – cis P-tau – that reveals a different tau protein pathology in VaD research.”

This innovative research has opened the door to new possible immunotherapies and has highlighted several new areas of research that need to be explored. Although the researchers delineated a pathway leading to the accumulation of cis P-tau, it is necessary to identify the underlying link between vascular abnormalities and pathway activation. A better understanding of how toxic cP-tau interacts with healthy trans P-tau could provide more information on the progression of AD disease.

AD and VaD may not be the only diseases affected by high levels of cis P-tau. Other brain disorders with a vascular component may also arise from this toxic protein, but further study will be needed to establish this link.

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

As we age and our memory begins to expire, losing car keys or forgetting the name of a new acquaintance, we fear the possibility that they are the first signs of dementia. And while there is currently no approved treatment to reverse the physiological effects of dementia, this new research can give hope that there are new therapies around the corner.


Women accumulate Alzheimer’s-related proteins more quickly


More information:
Chenxi Qiu et al, Cis P-tau underlies the vascular contribution to cognitive impairment and dementia and can be effectively targeted by immunotherapy in mice, Scientific translational medicine (2021). DOI: 10.1126 / scitranslmed.aaz7615

Citation: Don’t Forget Me: New Goal Shows Promise in Treatment of Alzheimer’s and Related Dementias (2021, June 10) Retrieved June 10, 2021 at https://medicalxpress.com/news/2021-06 -alzheimer-dementia.html

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