title: Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.
abstract: 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 β-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 sAPPβ 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 β-C-terminal fragment (β-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 β-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPPβ levels. Taken together, these data suggest that the physiopathological events underlying the chronic Aβ production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD.
authors.affiliation: Department of Neurology, Inst. Investigacions Biomediques, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Sant Antoni María Claret, 167, 08025 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pera
authors.forename: Daniel
authors.initials: D
authors.lastname: Alcolea
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.forename: Martí
authors.initials: M
authors.lastname: Colom-Cadena
authors.forename: Nahuai
authors.initials: N
authors.lastname: Badiola
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Barrera-Ocampo
authors.forename: Diego
authors.initials: D
authors.lastname: Sepulveda-Falla
authors.forename: Rafael
authors.initials: R
authors.lastname: Blesa
authors.forename: José L
authors.initials: JL
authors.lastname: Molinuevo
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid / Q000378:metabolism; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016501:Neurites / Q000473:pathology; D053764:Presenilin-1 / Q000134:cerebrospinal fluid / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human