Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter A beta production
Por:
Suarez-Calvet, M, Belbin, O, Pera, M, Badiola, N, Magrane, J, Guardia-Laguarta, C, Munoz, L, Colom-Cadena, M, Clarimon, J, Lleo, A
Publicada:
1 ene 2014
Resumen:
Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of A beta 42/40 and changed the product line preference of gamma-secretase towards A beta 38 production. In addition, the APP I716F mutation impaired the epsilon-cleavage and the fourth cleavage of gamma-secretase and led to abnormal APP beta-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position.
Filiaciones:
Suarez-Calvet, M:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Belbin, O:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Pera, M:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Badiola, N:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Magrane, J:
Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA
Guardia-Laguarta, C:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Munoz, L:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Colom-Cadena, M:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Clarimon, J:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
Lleo, A:
Univ Autonoma Barcelona, Dept Neurol, Memory Disorders Unit, Hosp Santa Creu & St Pau,IIB St Pau, E-08193 Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Alzheimer Lab, Barcelona 08025, Spain
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