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Title
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Inactivation of -secretases leads to accumulation of substrates and non-Alzheimer neurodegeneration
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Author
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Abstract
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| gamma-Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all -secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre(+)). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10-fold accumulation of membrane-bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of -secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane-bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a- or Aph1bc-secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1--secretase inhibitors should be considered for treatment of Alzheimer's disease. |
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Language
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English
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Source (journal)
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EMBO molecular medicine. - -
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Publication
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2017
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ISSN
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1757-4676
1757-4684
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DOI
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10.15252/EMMM.201707561
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Volume/pages
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9
:8
(2017)
, p. 1088-1099
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ISI
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000406702900008
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Full text (Publisher's DOI)
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