title: Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production.
abstract: 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 Aβ42/40 and changed the product line preference of γ-secretase towards Aβ38 production. In addition, the APP I716F mutation impaired the ε-cleavage and the fourth cleavage of γ-secretase and led to abnormal APP β-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. The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with γ-secretase cleavage. While all three mutations direct γ-secretase cleavage towards the 48→38 production line, the APP I716F mutation also impaired the ε-cleavage and the fourth cleavage of γ-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation.
authors.affiliation: Department of Neurology, Memory Disorders Unit, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Alzheimer Laboratory, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.forename: Olivia
authors.initials: O
authors.lastname: Belbin
authors.forename: Marta
authors.initials: M
authors.lastname: Pera
authors.forename: Nahuai
authors.initials: N
authors.lastname: Badiola
authors.forename: Jordi
authors.initials: J
authors.lastname: Magrané
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.forename: Laia
authors.initials: L
authors.lastname: Muñoz
authors.forename: Martí
authors.initials: M
authors.lastname: Colom-Cadena
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003062:Codon; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009154:Mutation
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003062:Codon; D053829:Amyloid Precursor Protein Secretases
keywords: APP mutations; Alzheimer's disease; amyloid-β peptide; presenilin; γ-secretase