Abstract
Mutations in presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD) by increasing production of the amyloidogenic form of amyloid β peptides ending at residue 42 (Aβ42). To identify a PS subdomain responsible for overproduction of Aβ42, we analyzed neuro2a cell lines expressing modified forms of PS2 that harbor an N1411 FAD mutation. Deletion or addition of amino acids at the C terminus and Ile448 substitution in PS2 with the N1411 FAD mutation abrogated the increase in Aβ42 secretion, and Aβ42 overproduction was de- pendent on the stabilization and endoproteolysis of PS2. The same C-terminal modifications in PS1 produced similar effects. Hence, we suggest that the C terminus of PS plays a crucial role in the overproduction of Aβ42 through stabilization of endoproteolytic PS derivatives and that these derivatives may be the pathologically active species of PS that cause FAD.
Original language | English |
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Pages (from-to) | 10627-10634 |
Number of pages | 8 |
Journal | Journal of Neuroscience |
Volume | 19 |
Issue number | 24 |
DOIs | |
Publication status | Published - Dec 15 1999 |
Externally published | Yes |
Keywords
- Amyloid β peptide
- Aβ42
- C terminus
- Endoproteolysis
- Familial Alzheimer's disease
- Presenilin 1
- Presenilin 2
- Stabilization
ASJC Scopus subject areas
- Neuroscience(all)