Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Abeta generation.

Department of Neurology, University of Bonn, 53127 Bonn, Germany.
Journal of Neuroscience (Impact Factor: 6.91). 02/2011; 31(5):1837-49. DOI: 10.1523/JNEUROSCI.2954-10.2011
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: In Alzheimer's disease (AD), abnormal sphingolipid metabolism has been reported, although the pathogenic consequences of these changes have not been fully characterized. We show that acid sphingomyelinase (ASM) is increased in fibroblasts, brain, and/or plasma from patients with AD and in AD mice, leading to defective autophagic degradation due to lysosomal depletion. Partial genetic inhibition of ASM (ASM(+/-)) in a mouse model of familial AD (FAD; amyloid precursor protein [APP]/presenilin 1 [PS1]) ameliorated the autophagocytic defect by restoring lysosomal biogenesis, resulting in improved AD clinical and pathological findings, including reduction of amyloid-β (Aβ) deposition and improvement of memory impairment. Similar effects were noted after pharmacologic restoration of ASM to the normal range in APP/PS1 mice. Autophagic dysfunction in neurons derived from FAD patient induced pluripotent stem cells (iPSCs) was restored by partial ASM inhibition. Overall, these results reveal a novel mechanism of ASM pathogenesis in AD that leads to defective autophagy due to impaired lysosomal biogenesis and suggests that partial ASM inhibition is a potential new therapeutic intervention for the disease.
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    ABSTRACT: Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome–lysosome fusion but because of inefficient autophago–lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions. Cell Death and Differentiation advance online publication, 31 January 2014; doi:10.1038/cdd.2014.4 Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell. 1 The impaired degradation of substrates in LSDs is assigned to lysosomal dysfunction. However, recent evidence indicates that deficient degradation in LSDs also derives from alterations in endosomal and autophagosomal pathways, which flow into the lysosomal system. 2 Autophagy is the process involved in the degradation of cytoplasmic organelles and cytosolic components. The best characterized kind of autophagy, macroautophagy, starts with the formation of an isolation membrane enveloping cytoplasmic cargoes to generate an autophagosome. The autophagosome then fuses with the lysosome to form an autophagolysosome. Cargo degradation takes place in this organelle by specific enzymes. 3,4 Deficiencies in different steps of the autophagic pathway have been recently described in several LSDs. 2 These evidences led to the hypothesis that removal of autophagic buildup could be a suitable approach to treat these diseases. However, these findings also underscored the need to independently define the nature of the autophagy impairment for each LSD. Because lipid storage characterizes many of these disorders, this research effort could also serve to define the poorly understood role of lipids in autophagy. Sphingolipidoses are LSDs for which autophagy analysis is scarce. 2 Niemann Pick disease type A (NPA) is a sphingo-lipidosis caused by loss of function mutations in the gene SMPD1 encoding for the acid sphingomyelinase (ASM). 5 This enzyme catalyzes sphingomyelin (SM) conversion into ceramide in lysosomes. 6 As a result of ASM deficiency, cells from NPA patients accumulate SM in their lysosomes. 7 The disease has a severe neurological involvement that leads to early death. 8 In mice lacking ASM (acid sphingomyelinase knockout mice, ASMko), which are a model for NPA, 9 gradual accumulation of SM occurs in brain lysosomes and at the plasma and synaptic membranes of neurons. 10,11 Here we have analyzed the autophagy–lysosomal systems in the brain of ASMko mouse and in fibroblasts from NPA patients. Our work demonstrates the existence of autophagy alterations in this disease, defines SM excess as a key determinant in these alterations and proposes strategies to revert them.
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