The thesis’ aim is to determine how adult neurogenesis is affected in Alzheimer’s disease (AD), through the identification of cross-talk interactions between neurogenesis and nerve growth factor (NGF) signaling during the onset and the progression of the neurodegeneration.
In AD animal models, neurogenesis has been reported to be altered, either increased or decreased in level, thus a unique and comprehensive interpretation of this phenomenon is far from being achieved. For this reason we aim to address this issue in the AD11 anti-NGF mouse model for NGF-deficit induced neurodegeneration. The work’s hypothesis is that a cross-talk between neurogenesis and NGF signaling might be involved in the onset and/or the progression of the disease.
I first analyzed the adult neurogenesis of AD11 mice in vivo. To this aim, the number of neural stem cells (NSCs) present in the subventicular zone (SVZ) of 6 months old control and transgenic animals was analyzed by BrdU labeling experiments and by the expression level of progenitor markers such as Dcx, Msi-1 and Sox2. Data showed that AD11 mice display a significant reduction in the number of SVZ NSCs. These results have been confirmed also in vitro, by performing neurosphere assays with progenitor cells derived from the SVZ of control and AD11 animals. By measuring their proliferative and differentiative potential, we showed that AD11 NSCs proliferate 10-fold less, with respect to their control counterparts, and display a significant impairment in their ability to differentiate into β-tubulin positive neurons, strongly suggesting a reduced adult neurogenesis in AD11 mice brains. Another aspects of this analysis is that AD11 NSCs are more responsive to NGF added to the neurospheres cultures. The overall results suggest that a link between impaired NGF signaling and altered neurogenesis could occur in human AD as well.
In the last part I also began the study of neurogenesis in dentate gyrus of hippocampus in control and AD11 mice.
