title: Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation.
abstract: We report the clinical, pathologic, and biochemical characteristics of the recently described amyloid precursor protein (APP) I716F mutation. We present the clinical findings of individuals carrying the APP I716F mutation and the neuropathologic examination of the proband. The mutation was found in a patient with Alzheimer disease with onset at the age of 31 years and death at age 36 years and who had a positive family history of early-onset Alzheimer disease. Neuropathologic examination showed abundant diffuse amyloid plaques mainly composed of amyloid-beta42 and widespread neurofibrillary pathology. Lewy bodies were found in the amygdala. Chinese hamster ovary cells transfected with this mutation showed a marked increase in the amyloid-beta42/40 ratio and APP C-terminal fragments and a decrease in APP intracellular domain production, suggesting reduced APP proteolysis by gamma-secretase. Taken together, these findings indicate that the APP I716F mutation is associated with the youngest age of onset for this locus and strengthen the inverse association between amyloid-beta42/40 ratio and age of onset. The mutation leads to a protein that is poorly processed by gamma-secretase. This loss of function may be an additional mechanism by which some mutations around the gamma-secretase cleavage site lead to familial Alzheimer disease.
authors.affiliation: Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Guardia-Laguarta
authors.forename: Marta
authors.initials: M
authors.lastname: Pera
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.forename: José Luis
authors.initials: JL
authors.lastname: Molinuevo
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Valle
authors.forename: Albert
authors.initials: A
authors.lastname: Lladó
authors.forename: Mireia
authors.initials: M
authors.lastname: Coma
authors.forename: Teresa
authors.initials: T
authors.lastname: Gómez-Isla
authors.forename: Rafael
authors.initials: R
authors.lastname: Blesa
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007532:Isoleucine / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009460:Neurologic Examination / Q000379:methods; D010649:Phenylalanine / Q000235:genetics*; D014162:Transfection / Q000379:methods
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007532:Isoleucine; D010649:Phenylalanine; D053829:Amyloid Precursor Protein Secretases