TY  - JOUR
AU  - Page, Richard M
AU  - Münch, Anna
AU  - Horn, Thomas
AU  - Kuhn, Peer-Hendrik
AU  - Colombo, Alessio
AU  - Reiner, Orly
AU  - Boutros, Michael
AU  - Steiner, Harald
AU  - Lichtenthaler, Stefan F
AU  - Haass, Christian
TI  - Loss of PAFAH1B2 reduces amyloid-β generation by promoting the degradation of amyloid precursor protein C-terminal fragments.
JO  - The journal of neuroscience
VL  - 32
IS  - 50
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.57413
M1  - DZNE-2020-03054
SP  - 18204-18214
PY  - 2012
AB  - Amyloid-β peptide (Aβ) is believed to play a central role in the pathogenesis of Alzheimer's disease. In view of the side effects associated with inhibiting the secretases that produce Aβ, new molecular targets are required to provide alternative therapeutic options. We used RNA interference (RNAi) to systematically screen the Drosophila genome to identify genes that modulate Aβ production upon knockdown. RNAi of 41 genes in Drosophila cells significantly lowered Aβ without affecting general secretion or viability. After the γ-secretase complex components, the most potent effect was observed for platelet activating factor acetylhydrolase α (Paf-AHα), and, in mammalian cells, the effect was replicated for its ortholog PAFAH1B2. Knockdown of PAFAH1B2 strongly reduced Aβ secretion from human cells, and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice. Reduced Aβ production was not attributable to altered β-amyloid precursor protein (APP) ectodomain shedding but was a result of an enhanced degradation of APP C-terminal fragments (CTFs) in the absence of PAFAH1B2 but not its close homolog PAFAH1B3. Enhanced degradation of APP CTFs was selective because no such effects were obtained for Notch or E-/N-cadherin. Thus, we have identified an important protein that can selectively modify Aβ generation via a novel mechanism, namely enhanced degradation of its immediate precursor. In view of the absence of a neurological phenotype in PAFAH1B2 knock-out mice, targeted downregulation of PAFAH1B2 may be a promising new strategy for lowering Aβ.
KW  - 1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics
KW  - 1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Animals
KW  - Drosophila
KW  - Gene Knockdown Techniques
KW  - HEK293 Cells
KW  - Humans
KW  - Mice
KW  - Mice, Knockout
KW  - Microtubule-Associated Proteins: genetics
KW  - Microtubule-Associated Proteins: metabolism
KW  - Peptide Fragments: metabolism
KW  - RNA Interference
KW  - Transfection
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Microtubule-Associated Proteins (NLM Chemicals)
KW  - Peptide Fragments (NLM Chemicals)
KW  - 1-Alkyl-2-acetylglycerophosphocholine Esterase (NLM Chemicals)
KW  - PAFAH1B1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23238734
C2  - pmc:PMC6621731
DO  - DOI:10.1523/JNEUROSCI.2681-12.2012
UR  - https://pub.dzne.de/record/136732
ER  -