Upregulation of PGC-1&#945; expression by Alzheimer's disease-associated pathway: presenilin 1/amyloid precursor protein (APP)/intracellular domain of APP.

Robinson, Ari; Grösgen, Sven; Mett, Janine; Zimmer, Valerie C; Haupenthal, Viola J; Hundsdörfer, Benjamin; Stahlmann, Christoph P; Slobodskoy, Yulia; Müller, Ulrike C; Hartmann, Tobias; Stein, Reuven; Grimm, Marcus O W

Upregulation of PGC-1α expression by Alzheimer's disease-associated pathway: presenilin 1/amyloid precursor protein (APP)/intracellular domain of APP.

Robinson, Ari; Grösgen, Sven; Mett, Janine; Zimmer, Valerie C; Haupenthal, Viola J; Hundsdörfer, Benjamin; Stahlmann, Christoph P; Slobodskoy, Yulia; Müller, Ulrike C; Hartmann, Tobias; Stein, Reuven; Grimm, Marcus O W.

Afiliación

Robinson A; Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.

Aging Cell ; 13(2): 263-72, 2014 Apr.

Article en En | MEDLINE | ID: mdl-24304563

RESUMEN

Cleavage of amyloid precursor protein (APP) by ß- and Î³-secretase generates amyloid-ß (Aß) and APP intracellular domain (AICD) peptides. Presenilin (PS) 1 or 2 is the catalytic component of the Î³-secretase complex. Mitochondrial dysfunction is an established phenomenon in Alzheimer's disease (AD), but the causes and role of PS1, APP, and APP's cleavage products in this process are largely unknown. We studied the effect of these AD-associated molecules on mitochondrial features. Using cells deficient in PSs expression, expressing human wild-type PS1, or PS1 familial AD (FAD) mutants, we found that PS1 affects mitochondrial energy metabolism (ATP levels and oxygen consumption) and expression of mitochondrial proteins. These effects were associated with enhanced expression of the mitochondrial master transcriptional coactivator PGC-1α and its target genes. Importantly, PS1-FAD mutations decreased PS1's ability to enhance PGC-1α mRNA levels. Analyzing the effect of APP and its Î³-secretase-derived cleavage products Aß and AICD on PGC-1α expression showed that APP and AICD increase PGC-1α expression. Accordingly, PGC-1α mRNA levels in cells deficient in APP/APLP2 or expressing APP lacking its last 15 amino acids were lower than in control cells, and treatment with AICD, but not with Aß, enhanced PGC-1α mRNA levels in these and PSs-deficient cells. In addition, knockdown of the AICD-binding partner Fe65 reduced PGC-1α mRNA levels. Importantly, APP/AICD increases PGC-1α expression also in the mice brain. Our results therefore suggest that APP processing regulates mitochondrial function and that impairments in the newly discovered PS1/APP/AICD/PGC-1α pathway may lead to mitochondrial dysfunction and neurodegeneration.

Asunto(s)

Enfermedad de Alzheimer/genética; Enfermedad de Alzheimer/patología; Precursor de Proteína beta-Amiloide/química; Precursor de Proteína beta-Amiloide/metabolismo; Presenilina-1/metabolismo; Factores de Transcripción/genética; Regulación hacia Arriba/genética; Animales; Encéfalo/metabolismo; Encéfalo/patología; Humanos; Ratones; Mitocondrias/metabolismo; Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma; Estructura Terciaria de Proteína; ARN Mensajero/genética; ARN Mensajero/metabolismo; Factores de Transcripción/metabolismo

Palabras clave

Alzheimer's disease; Fe65; PGC1-α; amyloid precursor protein intracellular domain; amyloid precursor protein processing; mitochondrial function

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Regulación hacia Arriba / Precursor de Proteína beta-Amiloide / Presenilina-1 / Enfermedad de Alzheimer Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Aging Cell Año: 2014 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido

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