PARTIAL REPROGRAMMING OF A GFAP-EXPRESSING SUBPOPULATION IN THE HIPPOCAMPAL SUBGRANULAR ZONE IMPROVES ADULT NEUROGENESIS AND COGNITION IN AGING MICE

Since 2006, it has been known that somatic cells can be reverted to a pluripotent state through induced expression of the Yamanaka transcription factors. Transient or partial expression of these factors can reverse age-associated cellular features without full dedifferentiation. In recent years, partial reprogramming has reversed multiple hallmarks of aging and age-related diseases in animal models. In the brain, however, its effects remain less understood and have mainly been studied using ubiquitous or broadly targeted neuronal reprogramming.
To investigate partial reprogramming in GFAP-expressing neural precursor cells, we generated a transgenic mouse model (GFAP-tTA/OSKM). Created by crossing TetO-OSKM and GFAP-tTA lines, this model uses a truncated GFAP promoter that is expressed predominantly in hippocampal progenitors, allowing the tTA transactivator to drive inducible expression of the reprogramming factors in the target cells. This approach makes it a valuable tool to assess the potential of partial reprogramming in adult neurogenesis.
Our results show that continuous induction of reprogramming from birth in this restricted cell population leads to a significant deterioration of hippocampal neurogenesis and to memory impairments, effects that are fully reversed when induction occurs in fully developed adult (11 months-old) individuals and in a cyclic manner. Moreover, induction of partial reprogramming in aged mice (20 months-old) results in an increase in adult neurogenesis accompanied by an improvement in memory performance.
Together, these findings demonstrate that the timing of partial reprogramming is a critical determinant of its effects in the brain, highlighting its potential to enhance neurogenesis and cognitive function during aging.