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Familial frontotemporal dementia-associated presenilin-1 c.548G>T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice.

Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G>T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G>T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G>T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, γ-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo γ-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G>T mutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G>V amino acid substitution does not affect γ-secretase activity. Finally, Psen1 c.548G>T(KI/KI);Psen2(-/-) mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G>T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression.

Pubmed ID: 22496554


  • Watanabe H
  • Xia D
  • Kanekiyo T
  • Kelleher RJ
  • Shen J


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

April 11, 2012

Associated Grants

  • Agency: NINDS NIH HHS, Id: R01 NS041783
  • Agency: NINDS NIH HHS, Id: R01 NS042818
  • Agency: NINDS NIH HHS, Id: R01 NS075346
  • Agency: NINDS NIH HHS, Id: R01NS041783
  • Agency: NIA NIH HHS, Id: RC2 AG036614
  • Agency: NIA NIH HHS, Id: RC2AG036614

Mesh Terms

  • Alleles
  • Amyloid Precursor Protein Secretases
  • Animals
  • Animals, Genetically Modified
  • Blotting, Northern
  • Blotting, Western
  • Brain
  • Cycloheximide
  • Enzyme-Linked Immunosorbent Assay
  • Frontotemporal Dementia
  • Maze Learning
  • Memory
  • Memory Disorders
  • Mice
  • Mutation
  • Presenilin-1
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • tau Proteins