Normal brain development in PS1 hypomorphic mice with markedly reduced γ-secretase cleavage of βAPP

R. Rozmahel, J. Huang, F. Chen, Y. Liang, V. Nguyen, M. Ikeda, G. Levesque, G. Yu, M. Nishimura, P. Mathews, S. D. Schmidt, M. Mercken, C. Bergeron, D. Westaway, P. St George-Hyslop

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Presenilin 1-null mice die at birth from brain and skeletal developmental deformities due to disrupted Notch signaling. Presenilin 1-null mice also have severely reduced γ-secretase cleavage of βAPP. The assumption has been that facilitation of Notch signaling and βAPP processing by presenilin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels (∼1% of normal) of mutant PS1-M146L. Homozygous mice have significantly reduced viability due to a Notch-like phenotype. The animals that survive have severe axial skeletal deformities and markedly diminished γ-secretase activity and accumulation of βAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated γ-secretase activity is not detrimental to normal brain development.

Original languageEnglish (US)
Pages (from-to)187-194
Number of pages8
JournalNeurobiology of Aging
Issue number2
StatePublished - 2002


  • Alzheimer's Disease
  • Gamma-secretase
  • Gene targeting
  • Mouse model
  • Notch signaling
  • Presenilin
  • β-amyloid precursor protein

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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