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Brain. 2015 Feb;138(Pt 2):440-55. doi: 10.1093/brain/awu354. Epub 2014 Dec 16.

Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease.

Author information

1
1 Université de Toulouse, UPS, Centre de Recherches sur la Cognition Animale, 118 route de Narbonne, F-31062 Toulouse Cedex 4, France 2 CNRS, Centre de Recherches sur la Cognition Animale, F-31062 Toulouse, France claire.rampon@univ-tlse3.fr.
2
1 Université de Toulouse, UPS, Centre de Recherches sur la Cognition Animale, 118 route de Narbonne, F-31062 Toulouse Cedex 4, France 2 CNRS, Centre de Recherches sur la Cognition Animale, F-31062 Toulouse, France 3 Laboratoire de Neurobiologie, ESPCI ParisTech, UMR 7637, Paris, France.
3
4 Department of Fundamental Neurosciences, University of Lausanne, Rue du Bugnon 9, CH-1005 Lausanne, Switzerland.
4
3 Laboratoire de Neurobiologie, ESPCI ParisTech, UMR 7637, Paris, France.
5
1 Université de Toulouse, UPS, Centre de Recherches sur la Cognition Animale, 118 route de Narbonne, F-31062 Toulouse Cedex 4, France 2 CNRS, Centre de Recherches sur la Cognition Animale, F-31062 Toulouse, France.
6
5 Stem Cell Laboratory for CNS Disease Modeling, Department of Experimental Medical Science, Wallenberg Neuroscience Centre, Lund University, BMC A10, 221 84 Lund, Sweden.

Abstract

In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement.

KEYWORDS:

Alzheimer’s disease; Neurod1; adult neurogenesis; hippocampus; memory

PMID:
25518958
DOI:
10.1093/brain/awu354
[Indexed for MEDLINE]

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