Research article

Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

Chera L Maarouf¹ , Ian D Daugs¹ , Salvatore Spina^2,3,4 , Ruben Vidal^2,3 , Tyler A Kokjohn^1,5 , R Lyle Patton¹ , Walter M Kalback¹ , Dean C Luehrs¹ , Douglas G Walker⁶ , Eduardo M Castaño⁷ , Thomas G Beach⁸ , Bernardino Ghetti^2,3 and Alex E Roher¹

¹  The Longtine Center for Molecular Biology and Genetics, Sun Health Research Institute, Sun City, AZ 85351, USA

²  Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA

³  Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

⁴  Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy

⁵  Department of Microbiology, Midwestern University, Glendale, AZ 85308, USA

⁶  Laboratory of Neuroinflammation, Sun Health Research Institute, Sun City, AZ 85351, USA

⁷  Fundacion Instituto Leloir, Buenos Aires, C1405BWE, Argentina

⁸  WH Civin Laboratory of Neuropathology, Sun Health Research Institute, Sun City AZ 85351, USA

author email corresponding author email

Molecular Neurodegeneration 2008, 3:20doi:10.1186/1750-1326-3-20

Published:	20 November 2008

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 γ-secretase activity to promote accumulation of toxic Aβ42 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-β precursor protein (AβPP), Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 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 Aβ40 over Aβ42. The AβPP 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.

Conclusion

These observations imply that missense mutations in PSEN genes can alter a range of key γ-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.