title: Amplifying mitochondrial function rescues adult neurogenesis in a mouse model of Alzheimer's disease.
abstract: Adult hippocampal neurogenesis is strongly impaired in Alzheimer's disease (AD). In several mouse models of AD, it was shown that adult-born neurons exhibit reduced survival and altered synaptic integration due to a severe lack of dendritic spines. In the present work, using the APPxPS1 mouse model of AD, we reveal that this reduced number of spines is concomitant of a marked deficit in their neuronal mitochondrial content. Remarkably, we show that targeting the overexpression of the pro-neural transcription factor Neurod1 into APPxPS1 adult-born neurons 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. Thus, since overexpression of Neurod1 into new neurons of APPxPS1 mice rescues spatial memory, our present data suggest that manipulating the mitochondrial system of adult-born hippocampal neurons provides neuronal plasticity to the AD brain. These findings open new avenues for far-reaching therapeutic implications towards neurodegenerative diseases associated with cognitive impairment.
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Richetin
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Moulis
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Millet
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Macarena S
authors.initials: MS
authors.lastname: Arràzola
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France; Department of Physiology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
authors.forename: Trinovita
authors.initials: T
authors.lastname: Andraini
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hua
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Noélie
authors.initials: N
authors.lastname: Davezac
authors.affiliation: Stem Cell Laboratory for CNS Diseases Modeling, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund Stem Cell Center and MultiPark, Lund University, BMC A10, 221 84 Lund, Sweden.
authors.forename: Laurent
authors.initials: L
authors.lastname: Roybon
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Belenguer
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Miquel
authors.affiliation: Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, France. Electronic address: claire.rampon@univ-tlse3.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Rampon
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D001678:Organelle Biogenesis; D011897:Random Allocation; D017208:Rats, Wistar
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C093564:Neurogenic differentiation factor 1
keywords: Adult neurogenesis; Alzheimer's disease; Dentate gyrus; Mitochondria; Neurod1