title: Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features.
abstract: Mutations of three different genes, encoding β-amyloid precursor protein (APP), presenilin 1 and presenilin 2 are associated with familial Alzheimer's disease (AD). Recently, the APP mutation A673V has been identified that stands out from all the genetic defects previously reported in these three genes, since it causes the disease only in the homozygous state (Di Fede et al. in Science 323:1473-1477, 2009). We here provide the detailed neuropathological picture of the proband of this family, who was homozygous for the APP A673V mutation and recently came to death. The brain has been studied by histological and immunohistochemical techniques, at the optical and ultrastructural levels. Cerebral Aβ accumulation and tau pathology were severe and extensive. Peculiar features were the configuration of the Aβ deposits that were of large size, mostly perivascular and exhibited a close correspondence between the pattern elicited by amyloid stainings and the labeling obtained with immunoreagents specific for Aβ40 or Aβ42. Moreover, Aβ deposition spared the neostriatum while deeply affecting the cerebellum, and therefore was not in compliance with the hierarchical topographical sequence of involvement documented in sporadic AD. Therefore, the neuropathological picture of familial AD caused by the APP recessive mutation A673V presents distinctive characteristics compared to sporadic AD or familial AD inherited as a dominant trait. Main peculiar features are the morphology, structural properties and composition of the Aβ deposits as well as their topographic distribution in the brain.
authors.affiliation: Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. giaccone@istituto-besta.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Fabio
authors.initials: F
authors.lastname: Moda
authors.forename: Mario
authors.initials: M
authors.lastname: Botta
authors.forename: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Andrea
authors.initials: A
authors.lastname: Uggetti
authors.forename: Marcella
authors.initials: M
authors.lastname: Catania
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Moro
authors.forename: Veronica
authors.initials: V
authors.lastname: Redaelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Spagnoli
authors.forename: Roberta Simona
authors.initials: RS
authors.lastname: Rossi
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Fede
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019943:Amino Acid Substitution / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000648:ultrastructure; D005808:Genes, Recessive / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D014633:Valine / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014633:Valine; D000409:Alanine