Abstract
BackgroundMutations 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.ResultsWe 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.ConclusionThese 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.
Highlights
Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD)
The presenilins are part of γsecretase, a heterotetrameric aspartyl membrane-bound protease complex comprised of four interacting molecules: PSEN, nicastrin, anterior pharynx defective 1 (Aph1) and presenilin enhancer 2 (Pen2) [4,5,6]
We investigated the differences among the PSEN mutations, as well as between the PSEN group and sporadic AD (SAD) or ND controls, with respect to Notch-1, N-cadherin and Erb-B4, molecules that are cleaved by the γ-secretase complex
Summary
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. Mutations in the presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes cause early-onset and aggressive forms of familial Alzheimer's disease (FAD). In humans the PSEN1 and PSEN2 genes are localized on chromosome 14 and chromosome 1, respectively, and encode for proteins with 65% amino acid sequence identity [1]. Presenilin-1 and PSEN2, 467 and 448 amino acids long, respectively, have nine transmembrane domains (TMD), two of which (TMD6 and TMD7) contain catalytic Asp residues at positions 257 and 385 forming an active center required for endoproteolysis [2,3]. Gamma-secretase interacts with more than 25 different substrates, potentially participating in a wide range of cellular functions [8,9,10,11]
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