Periodic Reporting for period 4 - Neurogenesis (Exploration and promotion of neurogenesis in the adult brain)
Reporting period: 2021-04-01 to 2022-03-31
There are many diseases that result in the loss of neurons and neurological impairment, for example stroke and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. There is today limited possibilities to treat these diseases and they often cause a high degree of functional impairment and much suffering These conditions mainly affect the elderly, and with an increasing proportion of the population in EU being of high age, this will be an increasing problem not only for the the afflicted individuals and their families, but also for society in terms of costs for care.
It is very important to find better treatments for conditions in which neurons are lost, and the overall objective of the project is to contribute knowledge that will facilitate the development of such new treatments.
We have characterised the molecular signals that allow astrocytes to generate neurons. Neurogenesis by astrocytes can be triggered by reducing signalling by the Notch pathway. We successfully demonstrated that this knowledge can be translated to promote replacement of neurons lost to stroke (or injury) by blocking Notch signalling in mice. A major technological achievement was the development of a strategy to uniquely label large numbers of individual neural stem/progenitor cells with expressed molecular barcodes, which allowed tracing clonal relationships between cells.
The results from these studies have been published in scientific journals and reported at conferences.
- Wheareas we and others previously had shown that astrocytes could give rise to neurons under certain conditions, it was not known whether this was the result of direct transdifferentiation of astrocytes to neurons, or whether the astrocytes gained stem cell properties. We found that the latter was true. This is quite remarkable and important as it demonstrates that there is a large reservoir of latent neural stem cells in the adult brain.
- At the onset of this project, we thought that the potential of astrocytes to generate neurons was restricted to the striatum, but we found that this is possible also in the cerebral cortex, when additional stimuli were added. This further expands the reservoir of latent neural stem cells available for possible therapeutic interventions.
- We identified a molecular pathway, the Notch signaling pathway, that regulates the transformation of astrocytes to neural stem cells and their initiation of neurogenesis. We demonstrated in an experimental model in mice that promote the replacement of lost neurons by inhibiting the Notch signaling pathway, as a proof of principle of a new paradigm for replacing lost neurons in neurological disease.