title: Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations.
abstract: BACKGROUND
  Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA.
  
  
  RESULTS
  We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations.
  
  
  CONCLUSIONS
  These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.
authors.affiliation: The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, AZ 85351, USA. alex.roher@bannerhealth.com.
authors.forename: Chera L
authors.initials: CL
authors.lastname: Maarouf
authors.forename: Ian D
authors.initials: ID
authors.lastname: Daugs
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spina
authors.forename: Ruben
authors.initials: R
authors.lastname: Vidal
authors.forename: Tyler A
authors.initials: TA
authors.lastname: Kokjohn
authors.forename: R Lyle
authors.initials: RL
authors.lastname: Patton
authors.forename: Walter M
authors.initials: WM
authors.lastname: Kalback
authors.forename: Dean C
authors.initials: DC
authors.lastname: Luehrs
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Walker
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Castaño
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Alex E
authors.initials: AE
authors.lastname: Roher