A new potential therapeutic target for Alzheimer’s disease (AD) has been discovered by US researchers based at Case Western Reserve University School of Medicine, Ohio. In a paper published this month in the journal Science Advances, the team describes how they discovered the role of a known pathway in the disruption of myelin production, a hallmark of AD. This new finding will be key to guiding future AD research which will explore how to target this pathway to intervene at easier stages of the disease, slowing its advance.
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Therapies needed to prevent the advancement of Alzheimer’s disease
AD is a form of dementia that is characterized by difficulties with memory, thinking, problem-solving, and language. Physically, the disease manifests in the brain, as an accumulation of plaques of amyloid-beta protein and misfolded and abnormally shaped tau proteins, alongside progressive nerve cell death.
While it was first identified over a century ago, the neurodegenerative disorder still has no known cure and its etiology is still unclear although age, genetics, and previous traumatic brain injury are known risk factors.
According to figures from the World Health Organization (WHO), Alzheimer’s is the most common form of dementia, of which there are 10 million new cases globally each year.
The current research from scientists at Case Western Reserve provides a route to developing new therapies before the cause of AD being confirmed. In identifying the pathway involved in disrupted myelin production, scientists will be able to focus their efforts on creating therapies aimed at preventing myelin degeneration at an early stage.
The role of the Drp1 protein
The study’s findings highlight the Drp1-HK1-NLRP3 pathway as being implicated in the disruption of the brain cells responsible for myelin sheath production, the protective white matter that coats the nerves. A wide body of evidence supports the role of oligodendrocytes (OLs) in producing myelin. In AD, OLs become dysfunctional and begin to die early on in the establishment of the disease.
Now, overexpression of the Drp1 protein within the Drp1-HK1-NLRP3 pathway has been highlighted as the culprit for this dysfunction in OLs. The results of the current study show that hyperactivation of the Drp1 protein initiates inflammation in the OLs, leading to reduced production in myelin.
With less myelination, the brain’s neural fibers cannot communicate as quickly as they need to. As the reduction in myelin production continues, as does the degradation of white matter, resulting in the cognitive impairment that is synonymous with AD.
Patients with AD often present a near-total degeneration of OLs at the time of diagnosis. With these new findings, scientists are hopeful that new therapies will be able to be developed by targeting and manipulating the Drp1-HK1-NLRP3 pathway. Such therapies would potentially prevent white matter degradation, and prevent the more serious cognitive symptoms for AD from developing. Already, Xin Qi, the study’s lead author, has worked with a team to patent a peptide inhibitor that is known to regulate the expression of Drp1.
Potential new therapies to prevent loss of white matter
The findings will likely be influenced by the next generation of AD therapies, as Qi highlights, “This is a missing part of the puzzle,".
We have discovered a pathway that is accessible to detection and potential treatment, prior to much of the disease's damage and well before clinical symptoms appear.”
As most patients with AD are not diagnosed until they have already lost a significant part of their brain’s white matter, the team is keen to use the knowledge accumulated in their new study to develop a therapy that would prevent this damage from occurring. However, the challenge will be identifying younger patients who may be at the beginning stages of developing AD.
Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease BY XINWEN ZHANG, RIHUA WANG, DI HU, XIAOYAN SUN, HISASHI FUJIOKA, KATHLEEN LUNDBERG, ERNEST R. CHAN, QUANQIU WANG, RONG XU, MARGARET E. FLANAGAN, ANDREW A. PIEPER, XIN QI, SCIENCE ADVANCES : EABB8680