Abstract
Beta amyloid peptides (Aβ) play a key role in the pathogenesis of Alzheimer disease (AD). Presenilins (PS) function as the catalytic subunits of γ-secretase, the enzyme that releases Aβ from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Familial Alzheimer disease (FAD)-linked PSEN mutations alter APP processing in a manner that increases the relative abundance of longer Aβ42 peptides to that of Aβ40 peptides. The mechanisms by which Aβ40 and Aβ42 peptides are produced in a ratio of ten to one by wild type presenilin (PS) and by which Aβ42 is overproduced by FAD-linked PS variants are not completely understood. We generated chimeras of the amyloid precursor protein C-terminal fragment (C99) and PS to address this issue. We found a chimeric protein where C99 is fused to the PS1 N-terminus undergoes in cis processing to produce Aβ and that a fusion protein harboring FAD-linked PS1 mutations overproduced Aβ42. To change the molecular interactions within the C99-PS1 fusion protein, we made sequential deletions of the junction between C99 and PS1. We found differential effects of deletion in C99-PS1 on Aβ40 and 42 production. Deletion of the junction between APP CTF and PS1 in the fusion protein decreased Aβ40, while it did not decrease Aβ42 production in the presence or absence of FAD-linked PS1 mutation. These results are consistent with the idea that the APP/PS interaction is differentially regulated during Aβ40 and 42 production.
Highlights
Alzheimer disease (AD) is a neurodegenerative disease characterized by the presence of senile plaques, of which beta amyloid peptide (Ab) is the primary component [1]
Consistent with endoproteolysis of the C99-PS1 fusion protein, we found that 6E10 monoclonal antibody (mAb) detected an,35 kDa NH2-terminal fragment (NTF) (Figure 1B)
We did not observe polypeptides smaller than 30 kDa in size when blots were probed with 6E10 mAb, indicating no fragmentation of amyloid precursor protein (APP) C-terminal fragment (CTF) from the fusion protein
Summary
Alzheimer disease (AD) is a neurodegenerative disease characterized by the presence of senile plaques, of which beta amyloid peptide (Ab) is the primary component [1]. Ab is considered to be involved in the pathogenesis of AD, because familial AD (FAD) has been linked to mutations in the genes that encode amyloid precursor protein (APP) [2,3,4] and presenilin (PS) [5,6,7] Mutations in these genes result in most cases in a relative increase in the production of Ab42 [8,9], which is the predominant form found in senile plaques [10]. The electron microscopic structure of purified, active c-secretase complex revealed a pore in the structure [16,17], but the structural resolution was too low to allow predictions about the working mechanisms It is unknown how Ab40/Ab42 are produced in a ratio of ten to one by wild type PS and how Ab42 is overproduced by FAD-linked PS variants. The nature of APPCTF/PS interaction during Ab40 and 42 production is not fully understood
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