alpha-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease
Por:
Agüero P, Sainz MJ, García-Ayllón MS, Saez J, Téllez R, Guerrero-López R, Pérez-Pérez J, Jiménez-Escrig A and Gómez-Tortosa E
Publicada:
31 oct 2020
Ahead of Print:
31 oct 2020
Resumen:
Background The disintegrin metalloproteinase 10 (ADAM10) is the main alpha-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive. Methods Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPP alpha and sAPP beta peptides. We evaluate variant's pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort. Results The mutation was absent from public databases and segregated with the disease. CSF A beta 42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPP alpha peptide, both compared to controls, while sAPP beta levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPP alpha and sAPP beta levels resembled those of controls. Therefore, a decreased sAPP alpha/sAPP beta ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened. Conclusions This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of alpha-secretase. This report encourages future research on ADAM10 enhancers.
Filiaciones:
Agüero P:
Department of Neurology, Fundación Jiménez Díaz, Avenida de los Reyes Católicos 2, 28040, Madrid, Spain
Sainz MJ:
Department of Neurology, Fundación Jiménez Díaz, Avenida de los Reyes Católicos 2, 28040, Madrid, Spain
:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Sant Joan d'Alacant, Spain
Unidad de Investigación, Hospital General Universitario de Elche, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Elche, Spain
Saez J:
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Sant Joan d'Alacant, Spain
Téllez R:
Department of Immunology, Fundación Jiménez Díaz, Madrid, Spain
Guerrero-López R:
Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD) and CIBERER, Madrid, Spain
Pérez-Pérez J:
Secugen S.L., Madrid, Spain
Jiménez-Escrig A:
Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain
Gómez-Tortosa E:
Department of Neurology, Fundación Jiménez Díaz, Avenida de los Reyes Católicos 2, 28040, Madrid, Spain.
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