Models of the human brain used to investigate the origins of Alzheimer’s disease and test new medicines

A new study published today in Advanced Science, spearheaded by researchers at City of Hope, describes the creation of a potent tiny brain platform for studying the molecular origins of Alzheimer’s disease and testing novel dementia treatments. Alzheimer’s drug development has hit snags due to a lack of knowledge about the pathological mechanisms that cause the disease, according to Herbert Horvitz Professor of Neuroscience Yanhong Shi, Ph.D., who also serves as director of the Beckman Research Institute’s Division of Stem Cell Biology Research. “This field’s preclinical research relies heavily on animal models, yet humans and rodents are very different, particularly in terms of brain anatomy. At City of Hope, we’ve developed a tiny brain model based on human stem cell research in order to better understand Alzheimer’s disease and perhaps discover cures.”

Using “brain organoids” produced from human induced pluripotent stem cell (hiPSC) technology, researchers at the City of Hope were able to simulate sporadic Alzheimer’s disease, which is the most prevalent type of the illness. Due to the fact that Alzheimer’s is a disease of old age, researchers gave the Alzheimer’s model mice serum to simulataneously breakdown of the blood-brain barrier with age. They next put the organoids through a series of tests to see whether they contained any of the well-known Alzheimer’s disease indicators, such as high amounts of amyloid plaques and tau tangles, as well as synaptic breakage associated with cognitive loss.

According to the Alzheimer’s Association, more than 6 million Americans have Alzheimer’s disease, which kills more people than both breast and prostate cancer combined. There are many others who are affected by this sad degenerative illness besides the person who has been diagnosed with it. There is presently no cure, and therapies available only treat the symptoms, not the underlying cause. Xianwei Chen, Ph.D., first author of the study and postdoctoral fellow at City of Hope’s Alzheimer’s disease research center, said, “Other studies using brain organoids used miniature brain models that are phenotypically young, but to truly understand what happens when Alzheimer’s strikes, we need to use age-associated models.” A strong platform for finding successful therapies for diseases affecting the human body’s most complex organ will be provided by our age-associated brain organoids, we think.

Studies in brain organoids showed that serum from the blood may cause several symptoms of Alzheimer’s disease when exposed to it preclinically. This suggests that treatments targeting multiple pathological changes, rather than just one, would be more successful in the long run. Most instances of Alzheimer’s disease are caused by late-onset or sporadic onset, according to the study (95 percent sporadic vs. 5 percent inherited). A single treatment, such as suppressing either amyloid or tau proteins, had no effect on the levels of tau or amyloid, indicating that these two important indicators influence disease development separately. Serum from blood, which simulates a leaky blood-brain barrier, may also induce synaptic breakage, which aid memory and healthy brain function. Translational Genomics Research Institute neurogenomics professor Matt Huentelman, Ph.D., stated that the City of Hope brain model offers a novel way to investigate potential therapies for this memory-robbing illness. Huentelman, a world authority on Alzheimer’s disease genetics who was not involved in this research, was not consulted. “Using the model established in this City of Hope-led research may assist expedite the assessment of possible treatment options, providing hope to Alzheimer’s patients and their families,” he added.

Journal Reference: Xianwei Chen, Guoqiang Sun, E Tian, Mingzi Zhang, Hayk Davtyan, Thomas G. Beach, Eric M. Reiman, Mathew Blurton‐Jones, David M. Holtzman, Yanhong Shi. Modeling Sporadic Alzheimer’s Disease in Human Brain Organoids under Serum ExposureAdvanced Science, 2021; 2101462 DOI: 10.1002/advs.202101462

Categories: Clinical