Investigating the role of hippocampal neurogenesis in Alzheimer's disease.

Neurogenesis is a form of plasticity that occurs constitutively in the neurogenic niches of the mammalian brain. Immature granule cells arising from adult hippocampal neurogenic niche, contribute to unique brain functions in rodents and recent evidences suggests that this process persists throughout life in mammals, including humans. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative diseases; most of them concentrate on Alzheimer’s disease. Given the fact the aetiology of this pathology is still unknown and several developed therapies are ineffective for the majority of patients, the study of hippocampal neurogenesis in this condition can provide insights and solutions. In this study we evaluate the neurogenic ability of OXS-N1. This small molecule was discovered as a pro-neurogenic compound through an in vitro phenotypic screening employing primary cell lines from the brain of postnatal mice. It was proven to increase both proliferation and neuronal differentiation of stem and progenitor cells of the two post-natal neurogenic niches. OXS-N1 was subsequently analysed in vivo in wild type mice and in a familial Alzheimer’s disease mouse model (5xFAD). After an evaluation of its effects on memory functions, here we perform an histological analysis on the brain tissues of these mice to assess the impact of OXS-N1 in the subgranular zone. The results we obtained indicate that OXS-N1 does not have the ability to increase the birth or survival of new neurones and neuroblasts, or to induce neural stem cells exit from quiescence. Nevertheless, these data provided an insight in the limitations of OXS-N1 applications in this experimental setting and pointed out the weaknesses of the workflow for the in vivo assessment of the drug’s effects on adult hippocampal neurogenesis.