Open AccessUpregulation of PGC ‐1α expression by A lzheimer's disease‐associated pathway: presenilin 1/amyloid precursor protein ( APP )/intracellular domain of APP
Author(s) -
Robinson Ari,
Grösgen Sven,
Mett Janine,
Zimmer Valerie C.,
Haupenthal Viola J.,
Hundsdörfer Benjamin,
P. Stahlmann Christoph,
Slobodskoy Yulia,
Müller Ulrike C.,
Hartmann Tobias,
Stein Reuven,
Grimm Marcus O. W.
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12183
Subject(s) - amyloid precursor protein , presenilin , biology , gene knockdown , intracellular , microbiology and biotechnology , mitochondrion , alpha secretase , downregulation and upregulation , messenger rna , biochemistry , gene , alzheimer's disease , medicine , disease
Summary Cleavage of amyloid precursor protein ( APP ) by β‐ and γ‐secretase generates amyloid‐β ( Aβ ) and APP intracellular domain ( AICD ) peptides. Presenilin ( PS ) 1 or 2 is the catalytic component of the γ‐secretase complex. Mitochondrial dysfunction is an established phenomenon in Alzheimer's disease ( AD ), but the causes and role of PS 1, 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 PS s expression, expressing human wild‐type PS 1, or PS 1 familial AD ( FAD ) mutants, we found that PS 1 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, PS 1‐ FAD mutations decreased PS 1's ability to enhance PGC ‐1α mRNA levels. Analyzing the effect of APP and its γ‐secretase‐derived cleavage products Aβ 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 / APLP 2 or expressing APP lacking its last 15 amino acids were lower than in control cells, and treatment with AICD , but not with Aβ, 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.