Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease
Por:
Pera, M, Alcolea, D, Sanchez-Valle, R, Guardia-Laguarta, C, Colom-Cadena, M, Badiola, N, Suarez-Calvet, M, Llado, A, Barrera-Ocampo, AA, Sepulveda-Falla, D, Blesa, R, Molinuevo, JL, Clarimon, J, Ferrer, I, Gelpi, E, Lleo, A
Publicada:
1 feb 2013
Resumen:
Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured beta-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPP beta and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP beta-C-terminal fragment (beta-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP beta-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPP beta levels. Taken together, these data suggest that the physiopathological events underlying the chronic A beta production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.
Filiaciones:
Pera, M:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Alcolea, D:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Sanchez-Valle, R:
Hosp Clin Barcelona, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Guardia-Laguarta, C:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Colom-Cadena, M:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Badiola, N:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Suarez-Calvet, M:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Llado, A:
Hosp Clin Barcelona, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Barrera-Ocampo, AA:
Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany
Univ Antioquia, Fac Med, Grp Neurociencias Antioquia, Medellin, Colombia
Sepulveda-Falla, D:
Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany
Univ Antioquia, Fac Med, Grp Neurociencias Antioquia, Medellin, Colombia
Blesa, R:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Molinuevo, JL:
Hosp Clin Barcelona, Dept Neurol, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Clarimon, J:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Ferrer, I:
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Barcelona, Hosp Univ Bellvitge, Inst Neuropatol, Serv Anat Patol,IDIBELL, Barcelona, Spain
Gelpi, E:
Biobanc Hosp Clin IDIBAPS, Neurol Tissue Bank, Barcelona, Spain
Lleo, A:
Univ Autonoma Barcelona, Hosp St Pau, Inst Invest Biomed, Dept Neurol, Barcelona 08025, Spain
CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Green Published, Hybrid Gold
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