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P3–405: Equimolar production of Abeta and AICD from C99 by gamma–secretase
Author(s) -
Funamoto Satoru,
Kakuda Nobuto,
Yagishita Sousuke,
Takami Mako,
Osawa Satoko,
Dohmae Naoshi,
Ihara Yasuo
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1676
Subject(s) - chemistry , blot , sf9 , cleavage (geology) , presenilin , mutant , western blot , microbiology and biotechnology , intracellular , microsome , biochemistry , in vitro , biology , recombinant dna , medicine , alzheimer's disease , paleontology , disease , spodoptera , fracture (geology) , gene
Background: Frontotemporal dementia (FTD) is frequently familial, however, only a subset of cases are caused by mutations in the microtubuleassociated protein tau (MAP ) gene (FTDP-17). Recently, mutations in the presenilin genes (PSEN1 and PSEN2) have been reported associated to familial FTD cases. Objective(s): To investigate the presence of PSEN1, PSEN2 and APP mutations in a sample of early onset familial FTD (f-EOFTD) patients recruited in southern Italy, without MAP gene mutations. Methods: 18 consecutive unrelated persons (7 females and 11 males; average onset age: 53.2 8.7 years, range 30-62 years) were diagnosed as affected by f-EOFTD. Familiarity was established through history; 10 patients belonged to autosomal dominant families and 8 showed at least a first and/or a second degree relative affected. Diagnostic procedures included clinical and neuropsychological examination, morphological and functional imaging, multiple diagnostic criteria, such as Lund-Manchester, NINCDS-ADRDA, Mc Keith and NINDS-AIREN criteria also modified for subcortical ischemic vascular dementia. Hachinski score was measured in each case. Coding regions of the MAPT, APP, PSEN1 and PSEN2 genes were sequenced in all affected subjects. APOE was also genotyped. Results: All patients showed decline of personal and social conduct, emotional blunting, loss of insight, inappropriate behavior, reduction of verbal fluency and of motor initiative. Neuropsychology evidenced a frontal profile characterized by executive dysfunction and verbal fluency reduction at earlier stage followed by memory impairment. Resonance Magnetic Imaging showed frontotemporal atrophy and Spect examination (on 11 out of 18 patients) hypoperfusion of the fronto-parieto-temporal lobes. No MAP and APP gene mutations were found. An Arg62His of PSEN2 gene (already reported in an AD patient) was identified in a 47-year-old female (onset at 32). A novel heterozygous substitution (G3A) resulting in an aminoacidic change from valine to isoleucine at codon 412 of the PSEN1 gene was detected in a 38-year-old female (onset at 30). Absence of Val412Ile was successively verified in 100 unrelated individuals, excluding it as common polymorphism. Conclusions: Presenilins analysis may be helpful in characterizing patients with f-EOFTD, particularly when MAP mutations are absent. Nevertheless, further studies are needed to establish the causality of PSENs mutations toward FTD.