1. Generation and deposition of Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease
- Author
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Harald Steiner, Armin Giese, Thomas Arzberger, Christian Haass, Benedikt Kretner, Janina Mielke, Akio Fukumori, Elisabeth Kremmer, Peer-Hendrik Kuhn, Stefan F. Lichtenthaler, and Johannes Trambauer
- Subjects
0301 basic medicine ,Mutant ,pathology [Frontal Lobe] ,Bioinformatics ,medicine.disease_cause ,pathology [Alzheimer Disease] ,0302 clinical medicine ,Amyloid precursor protein ,presenilin ,metabolism [Peptide Fragments] ,Mutation ,Microscopy ,biology ,Chemistry ,metabolism [Presenilin-1] ,Neurodegeneration ,neurodegeneration ,genetics [Presenilin-1] ,Alzheimer's disease ,Immunohistochemistry ,Frontal Lobe ,Cell biology ,amyloid‐β peptide 43 ,genetics [Mutant Proteins] ,Molecular Medicine ,Amyloid ,metabolism [Amyloid beta-Peptides] ,amyloid beta-protein (1-43) ,Presenilin ,03 medical and health sciences ,PSEN1 protein, human ,Alzheimer Disease ,Report ,mental disorders ,medicine ,Presenilin-1 ,Humans ,ddc:610 ,metabolism [Mutant Proteins] ,Loss function ,γ‐secretase ,Amyloid beta-Peptides ,medicine.disease ,Peptide Fragments ,nervous system diseases ,030104 developmental biology ,biology.protein ,Mutant Proteins ,030217 neurology & neurosurgery ,Reports ,Neuroscience - 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.
- Published
- 2016