Researchers at Washington University School of Medicine in St. Louis have developed a way to capture the effects of aging on the development of Alzheimer’s disease. They devised a method to study aging neurons in the lab without the need for a brain biopsy, an advance that could lead to a better understanding of the disease and new treatment strategies.
The scientists transformed skin cells taken from patients with late-onset Alzheimer’s into brain cells called neurons. Late-onset Alzheimer’s develops gradually over many decades and only begins to show symptoms after the age of 65. For the first time, these lab-derived neurons accurately reproduced the hallmarks of this type of dementia, including the buildup of beta amyloid, deposits of tau protein, and neuronal cell death.
By studying these cells, the researchers identified aspects of the cells’ genomes (called retrotransposable elements, which change their activity as we age) in the development of late-onset Alzheimer’s disease. The findings suggest new treatment strategies targeting these factors.
The study appears August 2 in the journal Science.
“Sporadic, late-onset Alzheimer’s disease is the most common type of Alzheimer’s disease, accounting for more than 95% of cases,” said senior author Dr. Andrew Yoo, professor of developmental biology. “It has been very difficult to study in the lab because of the complexity of the disease, which stems from several risk factors, including aging as a major factor. Until now, we didn’t have a way to capture the effects of aging on cells to study late-onset Alzheimer’s disease.”
To date, studies of Alzheimer’s disease in animals have, by necessity, focused on mice with rare genetic mutations known to cause early-onset inherited Alzheimer’s in younger people — a strategy that has shed light on the disease but differs from the development of the disease in the vast majority of patients with the late-onset sporadic form. To more faithfully recapitulate the disease in the lab, Yoo’s team turned to an approach called cellular reprogramming.
The method of transforming human skin cells easily obtained from living patients directly into neurons makes it possible to study the effects of Alzheimer’s on the brain without the risk of a brain biopsy and in a way that preserves the consequences of the patient’s age on the neurons. Previous work by Yoo and colleagues, who pioneered this transformation technique using small RNA molecules called microRNAs, has focused on understanding the development of Huntington’s disease, an inherited neurological condition that typically presents with adult-onset symptoms.
After transforming skin cells into neurons, the researchers found that the new neurons can grow in a thin layer of gel or self-assemble into small clusters, called spheroids, mimicking the three-dimensional environment of the brain. The researchers compared neural spheroids generated from patients with late-onset sporadic Alzheimer’s disease, inherited Alzheimer’s disease, and healthy individuals of similar ages.
Spheroids from Alzheimer’s patients rapidly developed deposits of beta amyloid and tau tangles between neurons. Activation of genes associated with inflammation also arose, and then neurons began to die, mimicking what is seen in brain scans of patients. Spheroids from older, healthy donors in the study showed some amyloid deposition, but much less than those from patients. The small amyloid deposits in the older, healthy spheroids are evidence that the technique is capturing the effects of age and suggest that the buildup of beta amyloid and tau was correlated with aging. It further demonstrates that the Alzheimer’s disease process makes the buildup much worse.
The researchers, including first author Zhao Sun, PhD, a scientist in Yoo’s lab, found that treating spheroids from patients with late-onset Alzheimer’s disease with drugs that interfere with the formation of amyloid beta plaques early in the disease process, before neurons begin to form a toxic buildup of amyloid beta, significantly reduced amyloid beta deposits. But treatment at later time points, when some buildup had already formed, had no effect or only modestly reduced later amyloid beta deposits. These data emphasize the importance of identifying and treating the disease early.
The study also found a role for retrotransposable elements (small pieces of DNA that jump to different locations in the genome) in the development of late-onset Alzheimer’s disease. Inhibiting these “jumping genes” with the drug lamivudine (also called 3TC), an antiretroviral drug that can dampen the activity of retrotransposable elements, had a positive effect: spheroids from patients with late-onset Alzheimer’s disease had fewer amyloid beta and tau tangles and showed less neuronal death compared with the same spheroids treated with a placebo. Lamivudine treatment had no beneficial effect on spheroids from patients with inherited early-onset Alzheimer’s disease, providing evidence that the sporadic development of aging-related late-onset Alzheimer’s disease has distinct molecular features compared with inherited autosomal dominant Alzheimer’s disease.
“In these patients, our new model system has identified a role for retrotransposable elements associated with the disease process,” Yoo said. “We were pleased to see that we could reduce the damage with a drug treatment that suppresses these elements. We look forward to using this model system as we work on novel personalized therapeutic interventions for late-onset Alzheimer’s disease.”
The researchers are planning future studies with spheroids that include multiple types of brain cells, including neurons and glia.
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 the neuropathology of late-onset Alzheimer’s disease by direct neuronal reprogramming. Science. August 2, 2024.
The University of Washington has filed a US patent application related to this work, titled “Three-dimensional direct neural reprogramming to model Alzheimer’s disease in human neurons,” under application number 020529/US-NP.
This work was supported by the Farrell Family Alzheimer’s Disease Fund; the Cure Alzheimer’s Fund; the Centene Fund; a Mallinckrodt Scholar Award; a Washington University Center for Neurogenomics and Informatics (NGI) Pilot Award; the Washington University Children’s Discovery Institute and St. Louis Children’s Hospital, grant numbers CDI-CORE-2015-505 and CDI-CORE-2019-813; the Barnes-Jewish Hospital Foundation, grant numbers 3770 and 4642; and the National Institutes of Health (NIH), grant numbers RF1AG056296, R01NS107488, R01AG0789640, and AG066444.