PT  - JOURNAL ARTICLE
AU  - Irfan Y. Tamboli
AU  - Heike Hampel
AU  - Nguyen T. Tien
AU  - Karen Tolksdorf
AU  - Bernadette Breiden
AU  - Paul M. Mathews
AU  - Paul Saftig
AU  - Konrad Sandhoff
AU  - Jochen Walter
TI  - Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation
AID  - 10.1523/JNEUROSCI.2954-10.2011
DP  - 2011 Feb 02
TA  - The Journal of Neuroscience
PG  - 1837--1849
VI  - 31
IP  - 5
4099  - http://www.jneurosci.org/content/31/5/1837.short
4100  - http://www.jneurosci.org/content/31/5/1837.full
SO  - J. Neurosci.2011 Feb 02; 31
AB  - Deposition of amyloid β peptides (Aβs) in extracellular amyloid plaques within the human brain is a hallmark of Alzheimer's disease (AD). Aβ derives from proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases. The initial cleavage by β-secretase results in shedding of the APP ectodomain and generation of APP C-terminal fragments (APP-CTFs), which can then be further processed within the transmembrane domain by γ-secretase, resulting in release of Aβ. Here, we demonstrate that accumulation of sphingolipids (SLs), as occurs in lysosomal lipid storage disorders (LSDs), decreases the lysosome-dependent degradation of APP-CTFs and stimulates γ-secretase activity. Together, this results in increased generation of both intracellular and secreted Aβ. Notably, primary fibroblasts from patients with different SL storage diseases show strong accumulation of potentially amyloidogenic APP-CTFs. By using biochemical, cell biological, and genetic approaches, we demonstrate that SL accumulation affects autophagic flux and impairs the clearance of APP-CTFs. Thus, accumulation of SLs might not only underlie the pathogenesis of LSDs, but also trigger increased generation of Aβ and contribute to neurodegeneration in sporadic AD.