title: A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia.
abstract: OBJECTIVE
  Soluble oligomers of amyloid beta (Abeta), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question.
  
  
  METHODS
  A Japanese pedigree showing Alzheimer's-type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on Abeta production, degradation, aggregation, and synaptotoxicity were also investigated.
  
  
  RESULTS
  We identified a novel APP mutation (E693Delta) producing variant Abeta lacking gulutamate-22 (E22Delta) in Japanese pedigrees showing Alzheimer's-type dementia and AD. Although the secretion of total Abeta was markedly reduced by this mutation, the variant Abeta was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but no fibrillization, and inhibited hippocampal long-term potentiation more potently than wild-type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant Abeta, a very low amyloid signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound-B.
  
  
  CONCLUSIONS
  The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.
authors.affiliation: Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Tomiyama
authors.forename: Tetsu
authors.initials: T
authors.lastname: Nagata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Rie
authors.initials: R
authors.lastname: Teraoka
authors.forename: Akiko
authors.initials: A
authors.lastname: Fukushima
authors.forename: Hyoue
authors.initials: H
authors.lastname: Kanemitsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takuma
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.forename: Masaki
authors.initials: M
authors.lastname: Imagawa
authors.forename: Suzuka
authors.initials: S
authors.lastname: Ataka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Eito
authors.initials: E
authors.lastname: Yoshioka
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005819:Genetic Markers