Cell replacement strategies in the central nervous system in two mouse models of neuronal damage: potential therapeutic targets and promising drugs

Abstract

The recent discovery of adult neural stem cells (NSC) has revealed the therapeutic potential of neurogenesis in the development of new regenerative therapies to treat the damaged adult brain. Physiologically, the generation of new neurons from NSC occurs mainly within two regions of the adult brain: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. However, the homeostatic mechanisms that lead to the generation of neurons can be modified under different pathological circumstances. We have studied in here two pathological conditions that affect neurogenesis in the SVZ and DG.

In response to cortical brain injuries, neurogenesis is stimulated in the SVZ, however no newly generated neurons can be found around the injury. Despite the attempt of neuroblasts to migrate toward the injury, they fail to cross the corpus callosum and reach the perilesional area. We have aimed in this thesis to understand the mechanisms impairing migration. Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF¿, activating the EGFR expressed in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway with the EGFR inhibitor Afatinib stimulates neuroblast migration toward the injury and leads to neuroblast enrichment within the injured area.

Likewise, neuropathological aging, is associated to cognitive decline and to alterations in neurogenesis in the DG. Neuropathology in the aged mouse brain alters the progeny of NSC leading to a larger number of astrocytes and to aberrant newly generated neurons. We have tested in here the effect of the small molecule ER272 in a murine model of neuropathological aging, the SAMP8 mouse. We show that in six-month-old SAMP8 mice, episodic and spatial memory are impaired, a reduced number of newly generated neurons is found, which show an aberrant morphology, and the generation of astrocytes is increased in this model. The treatment of SAMP8 mice with ER272 prevents these defects, positively regulating neurogenesis and improving cognitive performance. We have tried to elucidate the cellular mechanisms involved in its effect.

Finally, vitamin D deficiency has been shown to be an accelerating factor for the progression of the aging process, leading to cognitive impairment. We have reviewed the role that the Wnt signaling pathway plays in neurogenesis in the aged mouse brain and have analyzed the relation between vitamin D and Wnt signaling to hypothesize that vitamin D may play a role in positively regulating neurogenesis through Wnt signaling and maintaining cognitive performance.