Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds.
Recently it was proposed that the familial Alzheimer's disease (FAD) causing presenilin (PSEN) mutations PSEN1-L435F and PSEN1-C410Y do not support the generation of Aβ-peptides from the amyloid precursor protein (APP). This challenges the amyloid hypothesis and disagrees with previous work showing that PSEN1 FAD causing mutations generate invariably long Aβ and seed amyloid. We contrast here the proteolytic activities of these mutant PSEN alleles with the complete loss-of-function PSEN1-D257A allele. We find residual carboxy- and endo-peptidase γ-secretase activities, similar to the formerly characterized PSEN1-R278I. We conclude that the PSEN1-L435F and -C410Y mutations are extreme examples of the previously proposed "dysfunction" of γ-secretase that characterizes FAD-associated PSEN. This Matters Arising paper is in response to Xia et al. (2015), published in Neuron. See also the response by Xia et al. (2016), published in this issue.
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium.
Sarah
S
Veugelen
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Takashi
T
Saito
Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Takaomi C
TC
Saido
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium. Electronic address: lucia.chavezgutierrez@cme.vib-kuleuven.be.
Lucía
L
Chávez-Gutiérrez
VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KU Leuven), 3000 Leuven, Belgium; Institute of Neurology, University College London, London, WC1N 3BG, UK. Electronic address: bart.destrooper@cme.vib-kuleuven.be.
Bart
B
De Strooper
D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*; D061251:Primary Cell Culture
D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases