New Model of Alzheimer’s Reveals Genetic Changes Associated with Cell Aging Processes

Learn about how researchers made a more accurate model of Alzheimer's disease using skin cells.

What: To make a more accurate model, researchers turned skin cells from people with sporadic Alzheimer’s disease (AD) into neurons that closely resemble the age and disease characteristics of human brain cells affected by AD.

Where: Mertens et al., Age-dependent Instability of Mature Neuronal Fate in Induced Neurons from Alzheimer’s Patients, Cell Stem Cell, 2021.

BrightFocus Connection: The work of first author Jerome Mertens PhD, was supported by an Alzheimer’s Disease Research grant. He is a faculty member at both the University of Innsbruck (Austria) and the Salk Institute in La Jolla, CA. In addition, coauthor Douglas Galasko, MD, of the University of California, San Diego, is a member of the ADR Scientific Review Committee.

Why It Is Important: Most people with AD develop the sporadic form of the disease, which only affects older people. However, most laboratory models used to study Alzheimer’s use cells from people with a familial form of the disease, which strikes when people are relatively young. We therefore do not have a complete understanding of how age impacts the development of AD, even though we know that the aging process plays a role.

In a collaborative project led by the Salk Institute, researchers set out to make a more accurate model of sporadic AD. To do so, they took skin cells from people in their seventies and eighties with sporadic AD (along with age-matched controls) and turned them into neurons using DNA binding proteins to directly convert skin cells into neurons. They found that these neurons retain the characteristics of aged brain cells but express genetic markers of cell stress, cell growth, and de-differentiation, making them a more physiologically relevant model to study the age-dependent mechanisms that cause sporadic AD than those currently used.

Unlike other cell types, which can regenerate, neurons do not continue to grow and divide after early human development. Instead, they maintain the same mature, differentiated state for their (and our) entire life. But the AD neurons these researchers made seem to have lost some of their identity, reverting to an immature state like that observed during development. The researchers hypothesize that this effect may be a byproduct of dysregulated aging that impairs neuronal function, and that the phenomenon may lie behind other Alzheimer’s-related changes in the brain.

To determine whether the observed changes in directly converted neurons were a consequence of normal aging or distinct from aging while dependent on age, the scientists reprogrammed the same patients’ skin cells back to an embryonic state and then differentiated them into neurons. This process erases and resets the aging characteristics of the neurons, so even though these reprogrammed neurons were derived from elderly people with AD they did not exhibit the same aging characteristics as the neurons that were directly converted. They also did not show the AD specific changes observed in the directly converted neurons. In contrast, reprogrammed neurons from people with familial AD do continue to show characteristics of the disease. This new model system demonstrates that direct conversion is necessary in order to appropriately study sporadic AD, as only the old neurons made directly from old skin cells - not from reprogrammed skin cells - retain the AD signatures.

One important conclusion of this work is that AD-related neuronal changes may be driven in part by cell aging processes, including regression to an earlier, less-developed state. It’s almost as if the cells lose track of their identities as neurons, much like people with AD lose track of parts of their own identities. Although these observed AD changes may be caused by aging-like processes, this work demonstrates that they are not a part of normal aging. Further research may determine whether they can be stopped with new therapies.