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The adipocyte differentiation protein APMAP is an endogenous suppressor of Aß production in the brain.
Mosser, Sebastien; Alattia, Jean-René; Dimitrov, Mitko; Matz, Alexandre; Pascual, Justine; Schneider, Bernard L; Fraering, Patrick C.
Afiliación
  • Mosser S; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland.
  • Alattia JR; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland.
  • Dimitrov M; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland.
  • Matz A; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland.
  • Pascual J; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland.
  • Schneider BL; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland.
  • Fraering PC; Brain Mind Institute and School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH1015, Switzerland patrick.fraering@epfl.ch.
Hum Mol Genet ; 24(2): 371-82, 2015 Jan 15.
Article en En | MEDLINE | ID: mdl-25180020
The deposition of amyloid-beta (Aß) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Aß is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by γ-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notch receptors. Endogenous modulation of γ-secretase is pointed to be implicated in the sporadic, age-dependent form of AD. Moreover, specifically modulating Aß production has become a priority for the safe treatment of AD because the inhibition of γ-secretase results in adverse effects that are related to impaired Notch cleavage. Here, we report the identification of the adipocyte differentiation protein APMAP as a novel endogenous suppressor of Aß generation. We found that APMAP interacts physically with γ-secretase and its substrate APP. In cells, the partial depletion of APMAP drastically increased the levels of APP-CTFs, as well as uniquely affecting their stability, with the consequence being increased secretion of Aß. In wild-type and APP/ presenilin 1 transgenic mice, partial adeno-associated virus-mediated APMAP knockdown in the hippocampus increased Aß production by ∼20 and ∼55%, respectively. Together, our data demonstrate that APMAP is a negative regulator of Aß production through its interaction with APP and γ-secretase. All observed APMAP phenotypes can be explained by an impaired degradation of APP-CTFs, likely caused by an altered substrate transport capacity to the lysosomal/autophagic system.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Glicoproteínas de Membrana / Péptidos beta-Amiloides / Enfermedad de Alzheimer / Proteínas del Tejido Nervioso Límite: Animals / Female / Humans / Male Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2015 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Glicoproteínas de Membrana / Péptidos beta-Amiloides / Enfermedad de Alzheimer / Proteínas del Tejido Nervioso Límite: Animals / Female / Humans / Male Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2015 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido