Claus Munck Petersen

Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Vanessa Schmidt
  • ,
  • Katharina Baum
  • ,
  • Angelyn Lao
  • ,
  • Katja Rateitschak
  • ,
  • Yvonne Schmitz
  • ,
  • Anke Teichmann
  • ,
  • Burkhard Wiesner
  • ,
  • Claus Munck Petersen
  • Anders Nykjaer
  • Jana Wolf
  • ,
  • Olaf Wolkenhauer
  • ,
  • Thomas E Willnow
The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-β (Aβ) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Aβ production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles.
Original languageEnglish
JournalE M B O Journal
Volume31
Issue1
Pages (from-to)187-200
Number of pages14
ISSN0261-4189
DOIs
Publication statusPublished - 2012

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