BMI SEMINAR // New neurons for old brains : adult neurogenesis in Alzheimer’s disease

Adult hippocampal neurogenesis is strongly impaired in Alzheimer’s disease (AD). In several mouse models of AD, it was shown that altered memory performances are associated with hippocampal adult neurogenesis deficits. We have found that adult-born neurons of APPxPS1 mice exhibit reduced survival and altered synaptic integration due to a severe lack of dendritic spines. Interestingly, we revealed that this reduced number of spines is concomitant of a marked deficit in their neuronal mitochondrial content. Remarkably, by targeting the overexpression of the pro- neural transcription factor Neurod1 into APPxPS1 adult-born neurons we were able to restores not only their dendritic spine density, but also their mitochondrial content and the proportion of spines associated with mitochondria. Using primary neurons, a bona fide model of neuronal maturation, we identified that increases of mitochondrial respiration accompany the stimulating effect of Neurod1 overexpression on dendritic growth and spine formation. Reciprocally, pharmacologically impairing mitochondria prevented Neurod1-dependent trophic effects. Our findings indicate that manipulating mitochondrial may open new avenues for far-reaching therapeutic implications towards neurodegenerative diseases associated with cognitive impairment.