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Researchers led by City of Hope, a world-renowned research and treatment center for cancer, diabetes, and other life-threatening diseases, have developed a powerful miniature brain platform to study the mechanistic causes of the disease. ‘Alzheimer’s and dementia drug testing in development, reports a new study published today in Advanced Science.
“Drug development for Alzheimer’s disease has encountered challenges due to an incomplete understanding of the pathological mechanisms of the disease,” said Yanhong Shi, Ph.D., Herbert Horvitz Professor of Neuroscience and Director of the Stem Cell Biology Research Division in the Department of Developmental and Stem Cell Biology at the City of Hope Beckman Research Institute.
“Preclinical research in this area primarily uses animal models, but there is a huge difference between humans and animals such as rodents, especially when it comes to the architecture of the brain. We at City of Hope have created a miniature brain model that uses human stem cell technology to study Alzheimer’s disease and, hopefully, to help find cures for this devastating disease.
City of Hope researchers were able to model sporadic Alzheimer’s disease, the most common form of the disease, using “brain organoids” derived from human-induced pluripotent stem cell technology (hiPSC ). Because Alzheimer’s disease is a disease of aging, scientists exposed the models to serum to mimic the breakdown of the blood-brain barrier associated with aging. Then they passed the organoids through different experiments to test for known biomarkers of Alzheimer’s disease, including high levels of amyloid plaques and tau tangles as well as synaptic ruptures linked to cognitive decline, among other pathological phenotypes. caused by disease.
More than 6 million people live with Alzheimer’s disease, which kills more people than breast and prostate cancer combined, reports the Alzheimer’s Association. The heartbreaking degenerative disease affects not only the person diagnosed with the disease, but also their primary caregiver, family and friends. No cure currently exists, and the treatments available simply treat the symptoms rather than the root cause.
“Other studies using brain organoids to examine Alzheimer’s have used miniature brain models that are phenotypically young, but to really understand what happens when Alzheimer’s strikes, we have to use models associated with age, and that’s what we did in this research project when we exposed the miniature brains in serum, ”said Xianwei Chen, Ph.D., lead author of the study and postdoctoral fellow at City of Hope. “We believe that the age-associated brain organoids that we have generated will provide us with a powerful platform to find effective treatments for disorders affecting the most complex organ in the human body.”
Preclinical research using brain organoids has revealed that exposure to blood serum can induce multiple symptoms of Alzheimer’s disease, suggesting that combination therapies targeting multiple pathological alterations would likely be more effective than single-target therapies currently in use. development. The researchers studied late or sporadic Alzheimer’s disease, which accounts for most cases (95% sporadic versus 5% hereditary). They found that attempting a single therapy – for example by inhibiting only amyloid or tau proteins – did not reduce tau or amyloid levels, respectively, suggesting that these two key biomarkers are likely causing the progression of the disease independently. Plus, exposure to blood serum – which mimics a leaky blood-brain barrier – could cause breaks in synaptic connections that help the brain remember things and function properly.
Matt Huentelman, Ph.D., professor of neurogenomics at the Translational Genomics Research Institute (TGen), said the brain model developed by City of Hope offers a new avenue to examine emerging treatments for this memory-stealing disease. Huentelman is a leading expert in the genetic study of Alzheimer’s disease and was not part of that study.
“Using the model developed in this City of Hope-led study could help speed up the assessment of potential treatment options, giving Alzheimer’s patients and their families a new sense of hope,” he said. -he declares.
Reference: Chen X, Sun G, Tian E et al. Modeling of sporadic Alzheimer’s disease in human brain organoids under serum exposure. Advanced sci. 2021: 2101462. doi: 10.1002 / adv.202011462
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