Transforming Skin Cells into Neurons Leads to New Insights for Alzheimer’s

Induced Alzheimer's Cells
Bring me those cells, and I want them alive! These neurons derived from skin cells could provide key insights into the development of Alzheimer's.

Researchers at UC San Diego have created a new weapon in the fight against Alzheimer’s: living neurons in the lab. Lead by Laurence Goldstein, director of UCSD’s Stem Cell Program, the team of scientists took fibroblasts from skin tissue to create induced pluripotent stem cells (iPSCs), which can become any mature cell in the body, including nerve cells. By harvesting fibroblasts from patients with Alzheimer’s, Goldstein and his colleagues were able to produce neurons that displayed clear tendencies towards developing the disease. Typical research requires harvesting brain tissue from dead patients, but these living cells provide a unique opportunity to study Alzheimer’s while it is still being developed. If this technique becomes widely adopted it will give researchers all over the world the samples they need to better understand, and possibly defeat, Alzheimer’s.

To effectively fight an enemy, one needs to know how they live. Researchers have been trying to conquer Alzheimer’s for decades, and in that pursuit have found many different ways to study the disease. Yet examining actual cells that have Alzheimer’s is difficult. Doctors simply won’t cut into a patient’s brain and remove tissue they think is affected. At least, not while that patient is alive. Yet postmortem study examines cells long after the disease has taken its course. What researchers need is a reliable way to study how Alzheimer’s develops in living cells as it happens. That’s where Goldstein and his colleagues come in. Their technique can take cells from patients with Alzheimer’s and create neurons outside of their bodies to be studied in the lab. No more messy brain autopsies, just living cells waiting to be examined. In the video below, Goldstein discusses more of the reasoning behind this research, as well as his team’s success:

Recently published in Nature, the work done at UC San Diego involved a small sample group: just six human sources for the cells. Goldstein and colleagues collected fibroblasts from two patients with the rare Familial Alzheimer’s Disease that is linked to genetic predisposition, two patients with Sporadic Alzheimer’s (thought to be not as genetically dependent), and two healthy people with no histories of neural disease. These skin cells were transformed into iPSCs and then into neurons. Nearly all of these transformed cells showed the activity expected for living nerve cells, including forming synaptic contacts. Satisfied with the vitality of the cells, UCSD researchers examined them for chemical markers linked to Alzheimer’s. In patient’s with the familial form of the disease they found higher levels of amyloid-β, phospho-tau, and active glycogen synthase kinase-3β – all proteins associated with the illness. Cells from one of the patients with the Sporadic variation also displayed some of these chemical indicators. While still very preliminary, the research indicates that these stem cell derived neurons could be a viable platform for studying the mechanisms involved in the onset of Alzheimer’s.

This study builds off of techniques in stem cell research that have only become available in the last few years. Induced pluripotent stem cells were first created in 2006. The process typically involves taking mature cells and using retroviruses to genetically alter them to become stem cells. As Singularity Hub discussed, by 2009 scientists had begun to debate whether fat cells or skin cells (i.e. fibroblasts) were better for transforming into iPSCs. The iPSC process is a great example of how a new technology can arise quickly and have a disruptive (and positive) impact on a field of science.

Yet with their recent arrival has come concerns over side effects of using iPSCs. In research unrelated to this study, iPSCs have been linked to increased risks for cells developing into cancer. More relevant, perhaps, are other concerns that the techniques used to create iPSCs may (in general) affect the creation of proteins in the final cell. In other words, critics worry that all this cellular alchemy may alter those chemical markers that scientists like Goldstein hope to examine.

Whether or not those concerns prove valid, there’s still great hope for beating Alzheimer’s through studying artificially created neurons in the lab. Even if iPSCs prove problematic, there are other ways of creating human neurons from fibroblasts (some of which were used in earlier experiments that agree with the UCSD study). No matter what technique is used, however, at some point soon it is very likely that scientists will be able to take skin samples from a wide variety of Alzheimer’s patients and family members and create lab-ready nerve cell specimens for examination. It will be like peeking inside someone’s brain chemistry without actually needing their brain on hand. There’s no guarantee that studying these cells will yield successful treatments for Alzheimer’s, but it makes logical sense that if you want to stop the disease in patients before it becomes life-destroying you need to understand how the disease begins. There may be a key protein, or gene, that if blocked early, could keep the cell from developing Alzheimer’s. It’s too soon to tell, but not too soon to hope.

[image credit: UC San Diego]

[source: Israel et al Nature (2012), UC San Diego News]

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