RT Journal Article SR Electronic T1 Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 1837 OP 1849 DO 10.1523/JNEUROSCI.2954-10.2011 VO 31 IS 5 A1 Irfan Y. Tamboli A1 Heike Hampel A1 Nguyen T. Tien A1 Karen Tolksdorf A1 Bernadette Breiden A1 Paul M. Mathews A1 Paul Saftig A1 Konrad Sandhoff A1 Jochen Walter YR 2011 UL http://www.jneurosci.org/content/31/5/1837.abstract 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.