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Researchers at Case Western Reserve University’s medical school have identified a new target for the development of Alzheimer’s disease (AD) that could lead to therapies that focus on treating the neurodegenerative condition as it begins to progress.

The discovery helps support a promising approach to AD research: finding and manipulating processes earlier in the development of the disease in hopes of slowing its progress.

“This is a missing piece of the puzzle,” said Xin Qi, professor in the Department of Physiology and Biophysics at the School of Medicine and lead researcher on the study, which was just published in Science Advances. “We have discovered a pathway that is amenable to detection and possible treatment before much of the disease has been harmed and long before clinical symptoms appear.”

First identified more than 100 years ago, AD is an age-related neurodegenerative disorder associated with plaque buildup of amyloid beta protein and tangles of tau protein in the brain, and progressive nerve cell death. The cause of AD is unknown and the biggest risk factors for developing AD are age, genetics, and previous traumatic brain injury.

Before the defining pathological features of the disease are in place, potential therapeutics aimed at mitigating the white matter degeneration that affects normal brain circuit functions may target the new pathway identified by Path Western Reserve researchers.

“There is growing body of evidence in this area that AD develops much earlier than previously thought, most likely decades before our current ability to clinically diagnose the condition,” said study co-author Andrew A. Pieper, who Morley Mather Chair of Neuropsychiatry at the School of Medicine, Director of the Neurotherapeutic Center at the Harrington Discovery Institute at the University Hospitals.

“Detecting the disease – and possibly treating it – at its earlier stages will be critical to our fight against its devastating effects. The new avenue discovered by Dr. Qi’s lab could be targeted to target before the disease gets this far has progressed to cause cognitive problems, “said Pieper, also a psychiatrist at the Geriatrics Research Education and Clinical Center (GRECC) at Louis Stokes Cleveland VA Medical Center.

The Drp1 way

The researchers found that the signaling pathway known as Drp1-HK1-NLRP3 plays a key role in disrupting the normal function of brain cells that produce the protective white matter for nerves known as myelin.

The dysfunction and possible death of these myelin-producing cells – called oligodendrocytes (OLs) – are well-established early events in AD that lead to cognitive deficits.

The new findings shed light on how OLs go wrong: the overexpression of a particular protein (Drp1) within the recently discovered signaling pathway.

It is the hyperactivation of the Drp1 protein that causes inflammation and injury to OLs and leads to a reduction in myelin – a slowdown in communication in the brain – that leads to white matter degeneration and significant cognitive impairment.

What’s next? Aim with therapeutics

Nearly complete degeneration of OLs occurs before most patients experience common symptoms of AD.

Therefore, the researchers hope to steer the path with therapeutics that regulate the expression of Drp1 and thereby slow down or reduce the damage to myelin-producing OLs.

In fact, Qi’s lab has patented a small molecule known as a peptide inhibitor that regulates the expression of Drp1 – which slows down the degeneration of brain cells.

In the study published by Science Advances, researchers found that elimination of Drp1 expression in mouse models corrected the energy-related defect in OLs associated with overexpression of this protein. This approach also reduced activation of inflammatory OLs, decreased tissue damage at these brain sites, and improved cognitive performance.

“Our results are encouraging that targeting the Drp1-HK1-NLRP3 pathway and decreasing the expression of the Drp1 protein could help decrease the downstream cascade of abnormal brain functions associated with AD progression,” Qi said Laboratory has examined Drp1 for a decade, especially in Parkinson’s and Huntington’s. “

“If therapies that target this pathway can slow, stop, or even reverse the progression of AD in its early stages, there may be a reduction or delay in damage and impairment in the later stages,” Qi said.

Most AD diagnoses are made in people age 65 and over, so it can be difficult to identify the disease in younger patients. Many patients experience significant loss of brain white matter – central to cognition, emotion, and awareness – before they are diagnosed.

“By identifying how AD develops in the earliest processes, scientists can better understand how to focus research on possible solutions for patients,” Pieper said. “The results from the qi laboratory can help address AD earlier, potentially leading to better management of symptoms and progression.

“Since its discovery in 1907, there have been a very small number of approved drugs for AD. While these drugs increase neurotransmission for temporary symptomatic benefit, they do not help slow the progression of the disease,” said Beeper. “Identifying prior approaches to treating AD – such as this research – is critical to society as the extent of AD explodes with our aging population.”

Researchers validated the pathway discovery using mouse models and post mortem brain samples from AD patients.

Researchers discover a neuroprotective treatment for chronic traumatic brain injury

More information:
“Oligodendroglial Glycolytic Stress Eliminates Anti-Inflammatory Activation and Neuropathology in Alzheimer’s Disease” Science Advances (2020). DOI: 10.1126 / sciadv.abb8680 Provided by Case Western Reserve University

Quote: The New Path in Alzheimer’s Disease provides an earlier target for potential therapies (2020, December 4th), which will be available on December 5th, 2020 at https://medicalxpress.com/news/2020-12-pathway-alzheimer-disease -earlier-potential.html

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