Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice

David R. Borchelt, Michael K. Lee, Victoria Gonzales, Hilda H. Slunt, Tamara Ratovitski, Nancy A. Jenkins, Neal G. Copeland, Donald L. Price, Sangram S. Sisodia

Research output: Contribution to journalArticle

Abstract

The activities of presenilin 1 (PS1) and 2 modulate the proteolytic processing of amyloid precursor proteins to produce Aβ1-42, and mutations in these proteins are associated with an accelerated rate of Aβ deposition. PS1 and PS2 themselves are subject to a highly-regulated endoproteolytic cleavage to generate stable 27 kDa N-terminal and 17 kDa C-terminal fragments. Here, we examined the relationship between the regulated cleavage of PS1 and the acceleration of Aβ deposition in transgenic mice that co-express Mo/Hu APPswe and varied levels mutant PS1 (A246E variant). The steady-state levels of the N- and C-terminal fragments of mutant PS1 in mice expressing low levels of mRNA were similar to that of mice expressing high levels of mRNA. Only mice expressing high levels of transgene mRNA accumulated uncleaved full-length protein. In mice co-expressing low levels of PS1A246E mRNA with Mo/Hu APPswe the age of appearance of Aβ deposits was similar to that of mice co-expressing expressing Mo/Hu APPswe with very high levels of mutant PS1. Our findings demonstrate that the levels of accumulated human PS1 N- and C-terminal fragments do not increase in proportion to the level of transgene mRNA and that similarly, the magnitude by which mutant PS1 accelerates the deposition of β-amyloid is not proportional to the level of transgene expression.

Original languageEnglish (US)
Pages (from-to)171-177
Number of pages7
JournalNeurobiology of Aging
Volume23
Issue number2
DOIs
StatePublished - Feb 20 2002

    Fingerprint

Keywords

  • Alzheimer
  • Amyloid Deposition
  • Mutant Presenilin
  • Neuropathology
  • Transgenic Mice

ASJC Scopus subject areas

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

Cite this

Borchelt, D. R., Lee, M. K., Gonzales, V., Slunt, H. H., Ratovitski, T., Jenkins, N. A., Copeland, N. G., Price, D. L., & Sisodia, S. S. (2002). Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice. Neurobiology of Aging, 23(2), 171-177. https://doi.org/10.1016/S0197-4580(01)00280-9