Scientists have shown that long-term intermittent reprogramming limited to hippocampal neurons increases their fitness and improves cognitive function in a mouse model of Alzheimer’s disease [1].
Targeted in time and space
Partial cellular reprogramming is one of the hottest directions in longevity research for a reason: it allows to rejuvenate cells without driving them all the way to pluripotency, where they lose their identity. One of the ways that partial reprogramming can be achieved is through intermittent administration (“pulsing”) of reprogramming factors. This approach has produced increased lifespan and healthspan in various animal models [2].
Modern technologies now allow reprogramming to be limited not only by time but also by specific organs and cell types. For example, David Sinclair’s group demonstrated that partial reprogramming of retinal ganglion cells could restore vision after optic nerve injury [3]. However, the nervous system remains underexplored in this context. A new study by scientists at the University of Barcelona, published in Cell, aims to close this gap.
Reprogramming in utero
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The researchers began by investigating the effects of partial cellular reprogramming on brain development by administering OSKM to pregnant mice and limiting the expression to the nervous system.
The offspring of treated mice developed significantly larger brains, up to double the normal weight. To refine their approach, the researchers adjusted the protocol by using a lower dose of the inducing compound (doxycycline), which allowed them to preserve brain morphology and survival, even though the mice’s brains were still larger than those of the control group.
Professor del Toro, a leading author on the study, explains that “when Yamanaka’s factors are introduced during the developmental phase, more neurons are generated, and the brain is more voluminous. This translates into better motor and social activity in the adult stages.”
“These results,” he adds, “are explained by the fact that we made it possible for all brain cells to express these factors, including stem cells. It was very surprising to discover that, if we control the expression of these factors very precisely, we can also control the process of cell proliferation and obtain brains with a larger cerebral cortex without losing the correct structure and functions.”
Fitter neurons, better cognition
However, the main goal was to assess whether partial reprogramming in neurons could alleviate neurodegeneration. The researchers created a mouse model of Alzheimer’s disease with the ability to conditionally express Yamanaka factors in hippocampal neurons.
From 12 to 35 weeks of age, these mice followed an intermittent reprogramming protocol, with factor expression activated for three days each week. At eight months, a stage when this strain of mice typically displays severe Alzheimer’s-like symptoms, the researchers conducted behavioral, histological, and molecular tests.
They found that hippocampal neurons in the treated mice were healthier, with better dendritic spines and synapses compared to controls. Remarkably, the size and number of amyloid beta plaques, a key hallmark of Alzheimer’s, were greatly reduced. However, other Alzheimer’s-related markers, such as neuroinflammation and stress responses, remained unchanged.
The epigenetic age of neurons was substantially lower in the treated mice compared to controls. Most importantly, the treatment improved some cognitive functions, including cognitive flexibility and spatial memory.
Making smarter babies?
Professor Albert Giralt, another leading author, explains: “In this case, we induced the expression of Yamanaka factors only in mature neurons. As these cells do not divide, their number does not increase, but we identified many markers that indicate a process of neuronal rejuvenation.”
He adds: “In these rejuvenated neurons, we detected that the number of synaptic connections increases, the altered metabolism is stabilized, and the epigenetic profile of the cell is also normalized. All these changes have a very positive effect on their functionality as neurons.”
This study, which includes renowned geroscientist Manuel Serrano among its authors, suggests that partial reprogramming could offer a viable preventative strategy against Alzheimer’s disease. The findings related to reprogramming during brain development are equally intriguing, hinting at the possibility of enhancing the cognitive abilities of offspring in utero.
In this study, we demonstrate that transient reprogramming with YFs not only safely increases neural proliferation during mouse brain development but also prevents the development of AD-related features in adulthood. The increased proliferation leads to more neurons and glial cells, expanding the cortex and improving behavioral performance. At adult stages, we found that principal neurons in the hippocampus tolerate transient YF expression for several months. Instead, the expression of YFs prevented the development of several AD-related hallmarks and ameliorated some of the cognitive deficits in the 5xFAD mouse model. These findings enhance our understanding of YFs as a tool to modulate neural proliferation and highlight their potential use in brain disorders.
Literature
[1] Shen, Y. R., Zaballa, S., Bech, X., Sancho-Balsells, A., Rodríguez-Navarro, I., Cifuentes-Díaz, C., … & Del Toro, D. (2024). Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming. Cell Stem Cell.
[2] Macip, C. C., Hasan, R., Hoznek, V., Kim, J., Lu, Y. R., Metzger IV, L. E., … & Davidsohn, N. (2024). Gene therapy-mediated partial reprogramming extends lifespan and reverses age-related changes in aged mice. Cellular Reprogramming, 26(1), 24-32.
[3] Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., … & Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature, 588(7836), 124-129.
