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@ARTICLE{Page:136732,
      author       = {Page, Richard M and Münch, Anna and Horn, Thomas and Kuhn,
                      Peer-Hendrik and Colombo, Alessio and Reiner, Orly and
                      Boutros, Michael and Steiner, Harald and Lichtenthaler,
                      Stefan F and Haass, Christian},
      title        = {{L}oss of {PAFAH}1{B}2 reduces amyloid-β generation by
                      promoting the degradation of amyloid precursor protein
                      {C}-terminal fragments.},
      journal      = {The journal of neuroscience},
      volume       = {32},
      number       = {50},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.57413},
      reportid     = {DZNE-2020-03054},
      pages        = {18204-18214},
      year         = {2012},
      abstract     = {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.},
      keywords     = {1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics /
                      1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism /
                      Amyloid beta-Peptides: metabolism / Amyloid beta-Protein
                      Precursor: metabolism / Animals / Drosophila / Gene
                      Knockdown Techniques / HEK293 Cells / Humans / Mice / Mice,
                      Knockout / Microtubule-Associated Proteins: genetics /
                      Microtubule-Associated Proteins: metabolism / Peptide
                      Fragments: metabolism / RNA Interference / Transfection /
                      Amyloid beta-Peptides (NLM Chemicals) / Amyloid beta-Protein
                      Precursor (NLM Chemicals) / Microtubule-Associated Proteins
                      (NLM Chemicals) / Peptide Fragments (NLM Chemicals) /
                      1-Alkyl-2-acetylglycerophosphocholine Esterase (NLM
                      Chemicals) / PAFAH1B1 protein, human (NLM Chemicals)},
      cin          = {AG Lichtenthaler / AG Steiner / AG Haass old},
      ddc          = {610},
      cid          = {I:(DE-2719)1110006 / I:(DE-2719)1110000-1 /
                      I:(DE-2719)1110007},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:23238734},
      pmc          = {pmc:PMC6621731},
      doi          = {10.1523/JNEUROSCI.2681-12.2012},
      url          = {https://pub.dzne.de/record/136732},
}