title: Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease.
abstract: 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.
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Vanessa
authors: V
authors: Schmidt
authors: Katharina
authors: K
authors: Baum
authors: Angelyn
authors: A
authors: Lao
authors: Katja
authors: K
authors: Rateitschak
authors: Yvonne
authors: Y
authors: Schmitz
authors: Anke
authors: A
authors: Teichmann
authors: Burkhard
authors: B
authors: Wiesner
authors: Claus Munck
authors: CM
authors: Petersen
authors: Anders
authors: A
authors: Nykjaer
authors: Jana
authors: J
authors: Wolf
authors: Olaf
authors: O
authors: Wolkenhauer
authors: Thomas E
authors: TE
authors: Willnow
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human; D053829:Amyloid Precursor Protein Secretases