The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice

Paul H. Wen, Patrick R. Hof, Xiaoping Chen, Karen Gluck, Gregory Austin, Steven G. Younkin, Linda H. Younkin, Rita DeGasperi, Miguel A. Gama Sosa, Nikolaos K. Robakis, Vahram Haroutunian, Gregory A. Elder

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer's disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-labeled neural progenitor cells leading to fewer new β-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD.

Original languageEnglish (US)
Pages (from-to)224-237
Number of pages14
JournalExperimental Neurology
Volume188
Issue number2
DOIs
StatePublished - Aug 1 2004

Keywords

  • Bromodeoxyuridine
  • Familial Alzheimer disease
  • Presenilin 1

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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    Wen, P. H., Hof, P. R., Chen, X., Gluck, K., Austin, G., Younkin, S. G., Younkin, L. H., DeGasperi, R., Gama Sosa, M. A., Robakis, N. K., Haroutunian, V., & Elder, G. A. (2004). The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Experimental Neurology, 188(2), 224-237. https://doi.org/10.1016/j.expneurol.2004.04.002