A044 Premature aging of neural stem cells in Huntington disease

<h3></h3> An overall decline in neurogenesis is observed during physiological aging and in neurodegenerative disorders including Huntington disease (HD). While neural stem cells (NSCs) in the adult rodent subventricular zone (SVZ) generate new neurons throughout life, in the adult human brain this neurogenesis process persists with new interneurons, probably born in the nearby SVZ and addressed to the striatum. Interestingly, this striatal neurogenesis decreases in HD patients. Such decline can be attributed to the exhaustion of the NSCs pool from the SVZ, representing one of the aging hallmarks. We showed that mutant huntingtin protein decreases SVZ neurogenesis by altering NSCs properties. In vitro, NSCs demonstrate restricted potency including a limited capacity to self-renew and proliferate suggesting a decreased NSCs pool. We then hypothesized that the reduced neurogenesis may be due to accelerated aging features in HD. The observed increased levels of senescence-associated (SA)-β-galactosidase activity in HD NSCs support this aging theory. Therefore, we evaluated the efficacy of metformin treatment, a drug with anti-aging properties. In vitro, metformin restores functions altered by HD in NSCs. To address the efficacy of this therapy in vivo on HD mice, we needed a SVZ neurogenesis behavioral read-out. As neurogenesis in the SVZ is dedicated to the olfactory bulb and participates in olfaction, we assessed olfaction in HD mice. Our preliminary results suggest defects in olfaction in HD, as seen with age. Thus, understanding the regulation of NSCs in the SVZ may help to design new therapies to sustain neurogenesis in the old and diseased brain.