Longevity Briefs: Could We Cure Alzheimer’s By Reprogramming Neurons?

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

All of our cells have the same set of genes, so why do heart cells and brain cells look so different? The root of this ‘cellular identity’ lies in the epigenetic modifications that determine which genes are switched on or off. Further epigenetic modifications occur throughout life, and may contribute to ageing by activating or inactivating the wrong genes in the wrong cells. Epigenetic modifications can be erased, which causes the cell to be reprogrammed into a stem cell, losing its identity in the process. However, within the past few decades, scientists have figured out a way to reverse only age-related epigenetic modifications, without turning the cell back into a stem cell.

This process, known as partial reprogramming, has been shown to erase signs of ageing in cells, and has even been shown to extend lifespan in some animal models. Partial reprogramming is an exciting area of research, but its implementation in humans is fraught with challenges.

The discovery:

In this study, researchers wanted to see if partially reprogramming neurons might be a path to treating Alzheimer’s disease. To test this, they used a mouse model that is prone to developing Alzheimer’s-like problems. They used genetic techniques that would allow the researchers to switch on the production of a set of proteins called Yamanaka factors (which are responsible for epigenetic reprogramming), but only in the mice’s hippocampus. This is the brain region that is usually first affected by Alzheimer’s disease, leading to early symptoms of memory loss.

Treatment began when mice were 12 weeks old. After activating Yamanaka factors for 3 days a week, for 8 months, researchers found that the treated mice had healthier hippocampal neurons and less amyloid beta plaque (an important marker of Alzheimer’s) compared to controls. More importantly, the treatment group had improved cognitive function, including better spatial memory. Not all aspects of the disease were prevented, however. There were no significant differences between treated and control mice when it came to inflammation in the brain, which is another key element of Alzheimer’s disease.

The performance of mice in a maze test for spatial memory. The mice with Alzheimer’s-like disease (orange) perform significantly worse than control mice (grey) when given a control treatment (VEH, left). However, when Yamanaka factor expression is activated in both the controls and the Alzheimer’s mice, the two groups perform just as well (DOX, right).
*Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming*

While it wasn’t the main goal of their study, the researchers also reported some intriguing findings after activating partial reprogramming in the developing brains of mouse embryos. They found that the brains of such mice ended up becoming significantly larger than normal, with more neurons and more connections between neurons. Remarkably, the adult mice treated in this way had better cognitive function than normal, with better performance in motor and social tests.

The implications:

So, partial reprogramming appears to rejuvenate neurons and reduce the severity of an Alzheimer’s-like disease, at least when used preventatively. The neurons of these mice had more connections with other neurons, a healthier metabolism, and an epigenetic profile comparable to that of much younger cells. These are all changes that might be expected to lead to better performance even in mice lacking any form of neurodegenerative disease. As for the increased brain size and cognitive performance in mice treated as embryos, this seemed to be due to increased proliferation of neural progenitor cells during development. These are stem cells that can develop into either neurons or glial cells, the latter being the ‘janitors’ of the brain, supporting the neurons and removing unwanted debris, including amyloid beta.

We are unlikely to see partial reprogramming tried in humans for quite some time. Even though the mice in this study did not suffer any harm from the treatment, humans live a lot longer than the duration of this study and might suffer some unanticipated consequence that has not yet been observed in animal studies. Furthermore, the mice in this study had to be genetically engineered so that Yamanaka factors would be expressed only in neurons. That approach would not viable in humans – we would need to create a drug or gene therapy to produce the same outcome, which is a far more challenging prospect.