Researchers remain perplexed as to what causes dementia and how to treat and reverse the cognitive decline seen in patients. In a one-of-a-kind study, researchers at the Medical University of South Carolina (MUSC) and Beth Israel Deaconess Medical Center (BIDMC) at Harvard Medical School found that cis P-tau, a toxic, 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 in Science Transitional Medicine, define the molecular mechanism that causes an accumulation of this toxic protein. In addition, they have shown that a monoclonal antibody (mAb) which targets this toxic protein was able to prevent disease pathology and memory loss in preclinical models of type AD and VaD. Moreover, this treatment was even able to reverse cognitive disorders in a preclinical model of the AD type.
“We believe our findings not only discovered cis P-tau as a major early factor in previously unrecognized DA and DA, but also identified highly effective and specific immunotherapy to target this common disease driver for treat and prevent AD and AD at early stages, “mentioned Onder Albayram, Ph.D., co-lead author and assistant professor in the cardiology division of the medical department of MUSC.
âThe genomic landscape really adapts after this toxic protein goes out. It was a great discovery. ”
– Dr Onder Albayram
Aging is a normal part of life – we experience weakened bones and muscles, stiffened blood vessels, and some memory loss. But for about 50 million people in the world, these blackouts gradually worsen, eventually leading to a diagnosis of dementia.
Dementia is a generic term that covers AD, which accounts for 60-80% of cases; VaD, the second most common cause; and other less common pathologies. Currently, there is no effective treatment for AD. Interestingly, most cases of AD have a vascular component, suggesting a broader relationship between cognitive function and healthy brain vasculature. A better understanding of this relationship could provide a platform to discover 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-principal author and postdoctoral researcher at BIDMC, Harvard Medical School.
In a preclinical model of VaD, young mice showed signs of brain inflammation and memory loss within a month. However, treatment of these mice with cis P-tau mAb prevented neural degradation and cognitive decline for up to six months. In a separate preclinical model of AD, old mice exhibited severe cognitive impairment. Interestingly, this severe deficiency was significantly reversed when the mice received the cis P-tau mAb.
“These data show that cis P-tau may be an upstream pathogenic factor common to both diseases,” said Albayram.
“Cis P-tau may be a common, early, and pathogenic factor underlying traumatic brain injury, VaD, and AD.”
– Dr Chenxi Qiu.
It is often difficult to translate the information obtained from preclinical models for humans, but this study offers reasons for optimism. The accumulation of cis P-tau caused dramatic changes in the genetic architecture of affected cells in a VaD model; these changes were consistent with those seen in patients with AD. The researchers then showed that treatment with cis P-tau mAb reversed 85% to 90% of these changes, suggesting the potency of this potential therapy.
âThe genomic landscape really adapts after the extinction of this toxic protein,â Albayram said. “It was a great discovery.”
Not only are Albayram and Qiu excited about these results, but MUSC colleagues are already very excited about this work.
“I can go on and on on this paper,” said Adviye Ergul, MD, Ph.D., professor at the College of Medicine, Department of Pathology and Laboratory Medicine at MUSC. “They provide strong evidence that there is an accumulation of a specific form of the tau protein – cis P-tau – which highlights a pathology different from the tau protein in VaD research.”
This groundbreaking research opened the door to potential new immunotherapies and highlighted several new areas of research that need to be explored. While the researchers have delineated a pathway that leads to the accumulation of cis P-tau, the underlying link between vascular abnormalities and activation of the pathway needs to be identified. A better understanding of how toxic cis P-tau interacts with healthy trans P-tau could provide additional information on the progression of AD disease.
AD and VaD might not be the only diseases affected by high levels of cis P-tau. Other brain disorders with a vascular component could also arise from this toxic protein, but further study will be needed to establish such a link.
âCis P-tau may be a common, early and pathogenic factor underlying traumatic brain injury, VaD and AD,â Qiu said.
As we age and our memories start to fade – misplacing our car keys or forgetting the name of a new acquaintance – we fear the possibility that these are the first signs of dementia. And while there is currently no approved treatment to reverse the physiological effects of dementia, this new research may give hope that new therapies are just around the corner.