Pharmacotherapies targeted to neurogenesis in order to rescue cognitive performance in Down syndrome

Giacomini, Andrea (2018) Pharmacotherapies targeted to neurogenesis in order to rescue cognitive performance in Down syndrome, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie, 30 Ciclo. DOI 10.6092/unibo/amsdottorato/8353.
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Down syndrome (DS) is a genetic condition caused by the triplication of chromosome 21. The most invalidating feature of DS is intellectual disability (ID). Neurogenesis and dendritic maturation impairment are key determinants of ID in DS. To study DS, several mouse models have been created and the most used is the Ts65Dn mouse. Despite intense efforts, there are currently no therapies for DS. Considering the time course of brain development, pharmacotherapies should be carried as early as possible during the lifespan. The goal of this project was to establish whether neonatal treatment with “unexplored” molecules restores the major neurodevelopmental defects and cognitive performance in the Ts65Dn mouse model and whether their effect is retained after treatment cessation. I have explored the effects of different molecules administered to Ts65Dn mice during the neonatal period. ELND006, an inhibitor of γ-secratase. ELND006 blocks the formation of a small APP-derived peptide which inhibits the activity of the SHH pathway, thereby reducing neurogenesis. EGCG, a natural inhibitor of the kinase DYRK1A, whose overactivity in the DS brain negatively affects neurogenesis. 7,8-DHF, a natural mimetic of BDNF that by activating the TRKB receptor may compensate for the reduced levels of BDNF in the DS brain. ELND006 restored neurodevelopment of the hippocampal formation of Ts65Dn mice, and most of these effects were retained at one month after treatment cessation. EGCG had short-term but not long-term effects on hippocampal development and behavior. 7,8-DHF administered neonatally caused restoration of hippocampal development. Moreover, administration of 7,8-DHF from postnatal day 3 to adolescence led to a restoration of memory. These demonstrations may stimulate the design of clinical trials in DS with the molecule/s with the highest efficacy and the safest profile. This is the challenge that faces the community of preclinical researchers interested in DS: to transform a dream into reality.

Tipologia del documento
Tesi di dottorato
Giacomini, Andrea
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
Down syndrome; Neurogenesis; Early pharmacotherapies; Hippocampus; Ts65Dn mouse.
Data di discussione
18 Aprile 2018

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