Qualitative changes in human ?-secretase underlie familial Alzheimer's disease
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed ?-secretase activity in brain sa...
| Autores: | , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2015 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p10396 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10396 https://www.scopus.com/inward/record.uri?eid=2-s2.0-84973869254&doi=10.1084%2fjem.20150892&partnerID=40&md5=b5ed674b3919232a5801844f3796d5b8 |
| Access Level: | acceso abierto |
| Palabra clave: | amyloid precursor protein carboxypeptidase gamma secretase presenilin 1 amyloid PSEN1 protein, human secretase adult aged Alzheimer disease Article brain cell communication clinical article controlled study enzyme activity enzyme analysis familial Alzheimer disease familial disease female gene mutation heterozygote human human tissue intron male mutation onset age pathogenicity priority journal protein expression protein function protein processing qualitative analysis animal cell culture genetics knockout mouse metabolism middle aged pathology Western blotting Adult Aged Alzheimer Disease Amyloid Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Animals Blotting, Western Brain Carboxypeptidases Cells, Cultured Female Humans Male Mice, Knockout Middle Aged Mutation Presenilin-1 |
| Sumario: | Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed ?-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall ?-secretase activity levels, and therefore, loss of overall (endopeptidase) ?-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (?-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like ?-secretase activity with ?-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase- like ?-secretase activities. However and interestingly, a few SAD patient samples display ?-secretase dysfunction, suggesting that ?-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-ß (Aß) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aß products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations. © 2015 Szaruga et al. |
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