United States: Researchers at Washington University School of Medicine in St. Louis have pioneered a novel approach to elucidate the effects of aging on Alzheimer’s disease progression. This innovative method allows for the examination of aged neurons in a laboratory setting without the need for invasive brain biopsies, potentially enhancing our comprehension of the disease and paving the way for novel therapeutic strategies.
Some of the achieved molecular transformations include scientists’ conversion of skin cells from patients with late-onset Alzheimer’s disease to neurons. There is a slow-progressing form of Alzheimer’s, which may take decades to develop, and in the majority of cases, the symptoms begin at 65 years of age and older, According to Washington University School of Medicine in St Louis.
In a laboratory, it has created neurons that mimicked the entire concept of this dementia variety, including the formation of amyloid beta plaque, tau protein tangles, and neuronal death.
Studying these cells, such components of cells’ genomes as retrotransposable factors, which change their work during the aging process and are connected with the development of the late-onset form of Alzheimer’s disease, were discovered by scientists. These findings do propose new therapeutic approaches aimed at these elements.
The findings were printed in the Science journal on August 2.
“Sporadic, late-onset Alzheimer’s disease comprise the majority of Alzheimer’s disorders, at more than 95 percent,” said Dr Yoo, a professor of developmental biology, as WUSTL reported.
“The complexity of the disease, influenced by multiple risk factors including aging, has rendered it challenging to study in the laboratory. Until now, we lacked a method to capture the effects of aging in the cells to study late-onset Alzheimer’s.”
Historically, Alzheimer’s research utilizing animal models has focused on mice with rare genetic mutations that induce early-onset Alzheimer’s in younger individuals. While this approach has provided insights into the disease, it does not accurately reflect the disease development in the vast majority of patients with the sporadic, late-onset form. Yoo’s team employed a technique known as cellular reprogramming to more accurately replicate the disease in the lab.
This method, which converts easily accessible human skin cells from living patients directly into neurons, allows for the study of Alzheimer’s effects on the brain without the need for risky brain biopsies while preserving the age-related characteristics of the neurons.
Yoo and his colleagues, who pioneered this transformation technique using microRNAs, initially focused on understanding Huntington’s disease, an inherited neurological disorder that typically manifests in adulthood.
Upon transforming skin cells into brain cells, the researchers observed that these new neurons could either grow in a thin gel layer or self-organize into small clusters—termed spheroids—emulating the brain’s three-dimensional environment, according to WUSTL.
The researchers compared neuronal spheroids generated from patients with sporadic, late-onset Alzheimer’s disease, inherited Alzheimer’s disease, and healthy individuals of similar ages.
The spheroids from Alzheimer’s patients rapidly developed amyloid beta deposits and tau tangles between neurons. Additionally, genes associated with inflammation were activated, leading to neuronal death, mimicking observations in brain scans of patients. Spheroids from older, healthy donors exhibited some amyloid deposition but significantly less than those from patients.
The presence of small amyloid deposits in older, healthy spheroids indicates that the technique successfully captures age-related effects and suggests that amyloid beta and tau accumulation correlates with aging, with the Alzheimer’s disease process exacerbating this buildup.
The researchers, including first author Zhao Sun, PhD, a staff scientist in Yoo’s lab, discovered that treating spheroids from late-onset Alzheimer’s patients with drugs that inhibit amyloid beta plaque formation early in the disease process significantly reduced amyloid beta deposits. However, treatment at later stages, after some buildup had occurred, was less effective or only modestly reduced subsequent amyloid beta deposits. This underscores the importance of early disease detection and intervention.
The study also highlighted the role of retrotransposable elements—small DNA fragments that move to different genome locations—in late-onset Alzheimer’s disease development.
Inhibiting these “jumping genes” with the drug lamivudine (also known as 3TC), an anti-retroviral drug that suppresses retrotransposable elements, had a beneficial effect: spheroids from late-onset Alzheimer’s patients showed reduced amyloid beta and tau tangles and less neuronal death compared to those treated with a placebo, as per WUSTL.
Lamivudine treatment did not benefit spheroids from patients with early-onset, inherited Alzheimer’s, providing evidence that sporadic late-onset Alzheimer’s disease associated with aging has distinct molecular characteristics compared to inherited Alzheimer’s.
“In these patients, our novel model system has identified a role for retrotransposable elements in the disease process,” Yoo remarked.
“We were encouraged to find that we could mitigate the damage with a drug that suppresses these elements. We anticipate using this model system to develop new personalized therapeutic interventions for late-onset Alzheimer’s disease.”
The researchers plan future studies incorporating multiple brain cell types, including neurons and glia, into the spheroids.