Researchers have found a new method to study aging neurons in the lab, which eliminates the need for brain biopsies. This advancement can help create accurate models of how aging influences the onset of late-onset Alzheimer’s disease. By examining these cells, researchers have unearthed elements of the genetic structure—known as retrotransposable elements—that alter their behavior as we age, playing a role in the development of late-onset Alzheimer’s. This research opens up potential new approaches for treatment that focus on these genetic changes.
A team at Washington University School of Medicine in St. Louis has created a technique to simulate the effects of aging on the development of Alzheimer’s disease. Their innovative method allows them to examine aged neurons in a lab setting without requiring a brain biopsy, potentially enhancing our understanding of the disease and helping to devise new treatments.
The researchers converted skin cells from patients with late-onset Alzheimer’s disease into neurons. Late-onset Alzheimer’s is a progressive condition that typically does not manifest until individuals reach 65 or older. For the first time, these lab-grown neurons successfully replicated characteristic features of this type of dementia, such as the accumulation of amyloid beta, deposits of tau proteins, and the death of neuronal cells.
In their study, the scientists discovered that specific elements of the cells’ genomes—known as retrotransposable elements—exhibit different levels of activity as people grow older, contributing to the progression of late-onset Alzheimer’s disease. This insight could pave the way for innovative treatment strategies that target these elements.
The new research was published on August 2 in the journal Science.
“Sporadic, late-onset Alzheimer’s disease is the most prevalent type, accounting for over 95% of all Alzheimer’s cases,” explained senior author Andrew Yoo, PhD, a professor of developmental biology. “Studying this condition in a lab has been challenging due to its complexity and the various contributing risk factors, with aging being a significant one. Until now, we lacked a method to investigate the impact of aging on cells in the context of late-onset Alzheimer’s.”
Previously, animal studies aimed at understanding Alzheimer’s focused on mice with specific genetic mutations that lead to inherited early-onset Alzheimer’s in younger individuals. While this approach has shed light on certain aspects of the disease, it does not accurately represent the majority of cases that develop sporadically in older adults. To better model the disease in a laboratory setting, Yoo’s team employed a technique known as cellular reprogramming.
This new method involves converting easily accessible human skin cells from living patients into neurons, allowing for the study of Alzheimer’s effects without the risks associated with brain biopsies. This also ensures that the aged aspect of the neurons is maintained. Previous work by Yoo and his team has utilized small RNA molecules known as microRNAs to pioneer this transformation method, focusing initially on Huntington’s disease—another inherited neurological disorder with typically adult-onset symptoms.
Once the skin cells were reprogrammed into brain cells, the scientists observed that the new neurons could either thrive in a thin gel or spontaneously form small clusters, resembling small 3D brain structures called spheroids. They compared these spheroids from patients with sporadic late-onset Alzheimer’s, inherited Alzheimer’s, and healthy individuals of similar ages.
The spheroids from Alzheimer’s patients quickly displayed signs of amyloid beta accumulation and tau tangles forming between neurons. Additionally, there was an increase in gene activity linked to inflammation, followed by neuronal cell death, which parallels findings from brain scans of Alzheimer’s patients. In contrast, spheroids from older, healthy donors exhibited minimal amyloid deposits, indicating that while aging does contribute to some amyloid buildup, it is significantly worse in Alzheimer’s patients.
Furthermore, the research team—including first author Zhao Sun, PhD—found that treating the spheroids from late-onset Alzheimer’s patients with medications aimed at inhibiting amyloid beta plaque formation during the early stages of the disease drastically reduced these deposits. However, when treatment was initiated later, after some plaques had already formed, it had minimal or no impact on reducing amyloid beta levels. These results highlight the critical nature of identifying and addressing the disease in its early stages.
The study also revealed the involvement of retrotransposable elements—DNA segments that relocate within the genome—in the pathology of late-onset Alzheimer’s. Suppressing these “jumping genes” using lamivudine (also known as 3TC), an anti-retroviral medication, showed a positive effect: the spheroids from late-onset Alzheimer’s patients exhibited fewer amyloid beta and tau tangles, along with reduced neuronal death, compared to placebo-treated spheroids. Importantly, lamivudine offered no benefits for spheroids from early-onset, inherited Alzheimer’s patients, suggesting distinct molecular mechanisms for sporadic late-onset Alzheimer’s linked to aging compared to inherited forms of the disease.
“This new model system has helped us identify a role for retrotransposable elements in the disease process,” stated Yoo. “We are encouraged by the ability to mitigate damage through drug treatments targeting these elements. We look forward to further exploring this model as we strive to develop personalized therapies for late-onset Alzheimer’s.”
The team plans to conduct additional studies using spheroids composed of various brain cells, including neurons and glial cells.
Sun Z, Kwon J, Ren Y, Chen S, Walker CK, Lu X, Cates K, Karahan H, Sviben S, Fitzpatrick JA, Valdez C, Houlden H, Karch CM, Bateman RJ, Sato C, Mennerick SJ, Diamond MI, Kim J, Tanzi RE, Holtzman DM, Yoo AS. Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming. Science. Aug. 2, 2024.
A U.S. patent related to this research has been filed by Washington University, titled “Three-dimensional direct neural reprogramming to model Alzheimer’s disease in human neurons,” under application number 020529/US-NP.
This research received funding from the Farrell Family Fund for Alzheimer’s Disease; the Cure Alzheimer’s Fund; the Centene Fund; a Mallinckrodt Scholar Award; a Washington University NeuroGenomics and Informatics Center (NGI) Pilot Award; the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital, with grant numbers CDI-CORE-2015-505 and CDI-CORE-2019-813; the Foundation for Barnes-Jewish Hospital, grant numbers 3770 and 4642; and the National Institutes of Health (NIH), grant numbers RF1AG056296, R01NS107488, R01AG0789640, and AG066444.
