Open Accessγ‐secretase complexes containing caspase‐cleaved presenilin‐1 increase intracellular Aβ 42 /Aβ 40 ratio
Author(s) -
Hedskog Louise,
Petersen Camilla A. Hansson,
Svensson Annelie I.,
Welander Hedvig,
Tjernberg Lars O.,
Karlström Helena,
Ankarcrona Maria
Publication year - 2011
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2010.01208.x
Subject(s) - presenilin , intracellular , caspase , microbiology and biotechnology , cleavage (geology) , apoptosis , cytosol , amyloid precursor protein secretase , chemistry , amyloid precursor protein , caspase 3 , biology , programmed cell death , biochemistry , alzheimer's disease , enzyme , medicine , paleontology , disease , fracture (geology)
Markers for caspase activation and apoptosis have been shown in brains of Alzheimer’s disease (AD) patients and AD‐mouse models. In neurons, caspase activation is associated with elevated amyloid β‐peptide (Aβ) production. Caspases cleave numerous substrates including presenilin‐1 (PS1). The cleavage takes place in the large cytosolic loop of PS1‐C‐terminal fragment (PS1CTF), generating a truncated PS1CTF lacking half of the loop domain (caspCTF). The loop has been shown to possess important regulatory functions with regard to Aβ 40 and Aβ 42 production. Previously, we have demonstrated that γ‐secretase complexes are active during apoptosis regardless of caspase cleavage in the PS1CTF‐loop. Here, a PS1/PS2‐knockout mouse blastocyst‐derived cell line was used to establish stable or transient cell lines expressing either caspCTF or full‐length CTF (wtCTF). We show that caspCTF restores γ‐secretase activity and forms active γ‐secretase complexes together with Nicastrin, Pen‐2, Aph‐1 and PS1‐N‐terminal fragment. Further, caspCTF containing γ‐secretase complexes have a sustained capacity to cleave amyloid precursor protein (APP) and Notch, generating APP and Notch intracellular domain, respectively. However, when compared to wtCTF cells, caspCTF cells exhibit increased intracellular production of Aβ 42 accompanied by increased intracellular Aβ 42 /Aβ 40 ratio without changing the Aβ secretion pattern. Similarly, induction of apoptosis in wtCTF cells generate a similar shift in intracellular Aβ pattern with increased Aβ 42 /Aβ 40 ratio. In summary, we show that caspase cleavage of PS1 generates a γ‐secretase complex that increases the intracellular Aβ 42 /Aβ 40 ratio. This can have implications for AD pathogenesis and suggests caspase inhibitors as potential therapeutic agents.