Transient Reprogramming in the Hippocampus is Protective in a Mouse Model of Alzheimer's Disease
Efforts to produce therapies based on cellular reprogramming aim to restore cell function without changing cell state. The original reprogramming research involved the production of induced pluripotent stem cells from somatic cells via expression of the Yamanaka factors, recapturing a process that takes place in early embryonic development. Since then, researchers have found that transient, partial reprogramming can restore youthful epigenetic patterns and behaviors in aged cells without the change of state, and the question is now how to constrain this partial reprogramming activity in a useful way in a living organism. A perhaps surprisingly large fraction of the work currently taking place on cellular reprogramming is aimed at the brain and nervous system. As an example of this sort of work, researchers here show that expression of the Yamanaka factors in the adult mouse hippocampus is protective against the pathology induced in a mouse model of Alzheimer's disease.
Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we employed a controlled spatiotemporal induction of YFs in the mouse brain across two distinct scenarios: during brain development and in adult stages within the context of neurodegeneration. Our focus on the impact of YFs on neurogenesis during development was influenced by recent findings that a subset of these factors is expressed in various neural progenitors early in this phase.
Here, we report that transient, low-level expression of YFs increased proliferation, resulting in an augmented output of neurons and glia, which led to an enlarged neocortex. This expansion was functionally reflected in enhanced motor and social behavior in adult mice. Because this induction protocol enhanced cognitive skills, we hypothesized that it could exert a similar effect in the context of a neurodegenerative disorder. Thus, we expressed YFs only in mature hippocampal neurons, using the 5xFAD mouse model of Alzheimer's disease. We show that these neurons tolerate intermittent YF expression while preserving their identity. This safe approach led to cognitive, molecular, and histological improvements in the 5xFAD mice.
Our results establish transient YF induction as a powerful tool for modulating neural proliferation, and it may open new therapeutic strategies for brain disorders.
I don't understand how they can control the dose on a celular level.