Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features.
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.
Giaccone
Giorgio
G
Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. giaccone@istituto-besta.it
Morbin
Michela
M
Moda
Fabio
F
Botta
Mario
M
Mazzoleni
Giulia
G
Uggetti
Andrea
A
Catania
Marcella
M
Moro
Maria Luisa
ML
Redaelli
Veronica
V
Spagnoli
Alberto
A
Rossi
Roberta Simona
RS
Salmona
Mario
M
Di Fede
Giuseppe
G
Tagliavini
Fabrizio
F
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D014633:Valine; D000409:Alanine