title: Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease.
abstract: As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-β peptide (Aβ) species, which are released from a C-terminal amyloid precursor protein fragment by γ-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the Aβ42 to Aβ40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD We now show that the very little Aβ generated by PS1 L435F consists primarily of Aβ43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Aβ43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found Aβ43-containing plaques in brains of patients with this mutation. The aberrant generation of Aβ43 by this particular mutant provides a direct objection against the presenilin hypothesis.
authors.affiliation: Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kretner
authors.affiliation: Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Trambauer
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Mielke
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Neuroproteomics, Klinikum rechts der Isar and Institute for Advanced Study, Technische Universität München, Munich, Germany.
authors.forename: Peer-Hendrik
authors.initials: PH
authors.lastname: Kuhn
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Neuroproteomics, Klinikum rechts der Isar and Institute for Advanced Study, Technische Universität München, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
authors.affiliation: Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: DZNE - German Center for Neurodegenerative Diseases, Munich, Germany Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arzberger
authors.affiliation: Biomedical Center, Metabolic Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany DZNE - German Center for Neurodegenerative Diseases, Munich, Germany harald.steiner@med.uni-muenchen.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D005625:Frontal Lobe / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008853:Microscopy; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D050505:Mutant Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C098994:amyloid beta-protein (1-43)
keywords: Alzheimer's disease; amyloid‐β peptide 43; neurodegeneration; presenilin; γ‐secretase