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

Richetin, Kevin; Leclerc, Clémence; Toni, Nicolas; Gallopin, Thierry; Pech, Stéphane; Roybon, Laurent LU and Rampon, Claire (2015) In Brain 138. p.440-455
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... (More)
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. (Less)
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author
organization
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publication status
published
subject
in
Brain
volume
138
pages
440 - 455
publisher
Oxford University Press
external identifiers
  • pmid:25518958
  • wos:000350209900030
  • scopus:84922379340
ISSN
1460-2156
DOI
10.1093/brain/awu354
language
English
LU publication?
yes
id
0b663451-fc99-499d-8374-64187cb5ebda (old id 4908024)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25518958?dopt=Abstract
date added to LUP
2015-01-07 15:31:44
date last changed
2017-11-12 03:14:49
@article{0b663451-fc99-499d-8374-64187cb5ebda,
  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.},
  author       = {Richetin, Kevin and Leclerc, Clémence and Toni, Nicolas and Gallopin, Thierry and Pech, Stéphane and Roybon, Laurent and Rampon, Claire},
  issn         = {1460-2156},
  language     = {eng},
  pages        = {440--455},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease.},
  url          = {http://dx.doi.org/10.1093/brain/awu354},
  volume       = {138},
  year         = {2015},
}