期刊
EMBO MOLECULAR MEDICINE
卷 8, 期 5, 页码 458-465出版社
WILEY-BLACKWELL
DOI: 10.15252/emmm.201505952
关键词
Alzheimer's disease; amyloid- peptide 43; -secretase; neurodegeneration; presenilin
资金
- Friedrich-Baur-Stiftung
- Deutsche Forschungsgemeinschaft [FOR2290]
- Breuer Foundation
- European Research Council under the European Union/ERC [321366-Amyloid]
As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid- peptide (A) species, which are released from a C-terminal amyloid precursor protein fragment by -secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the A42 to A40 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 A generated by PS1 L435F consists primarily of A43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of A43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found A43-containing plaques in brains of patients with this mutation. The aberrant generation of A43 by this particular mutant provides a direct objection against the presenilin hypothesis.
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