Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs

Naoyuki Sato, Masayasu Okochi, Mitsuru Shinohara, Gopal Thinakaran, Shuko Takeda, Akio Fukumori, Motoko Shinohara-Noma, Mari Mori-Ueda, Hizuki Hamada, Masatoshi Takeda, Hiromi Rakugi, Ryuichi Morishita
PloS One 2012, 7 (11): e48551
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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"