Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

Tamboli, Irfan Y.; Hampel, Harald; Tiên, Nguyễn Thành; Tolksdorf, Karen; Breiden, Bernadette; Mathews, Paul M.; Säftig, Paul; Sandhoff, Konrad; Walter, Jochen

doi:10.1523/jneurosci.2954-10.2011

Cited by 86 publications

(82 citation statements)

References 78 publications

(83 reference statements)

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“…24 Increased ganglioside levels promote autophagy initiation and do not affect autophagosome-lysosome fusion but impair efficient clearance in different sphingolipidosis. 23 We here identify SM as a relevant lipid in autophagy regulation. We show that changes in these lipid levels do not alter autophagy initiation or lysosomal fusion with endocytic and autophagic vesicles …”

Section: Discussionmentioning

confidence: 84%

“…It has been proposed that altered lipid content (i.e., high cholesterol or ganglioside levels) may contribute to autophagy impairment. [20][21][22][23][24] On the other hand, the lipid that most significantly accumulates in neurons from ASMko mice is SM. 10 Hence, we directly tested whether SM accumulation was responsible for the autophagosome-lysosome alterations observed in the ASMko mice brain.…”

Section: Resultsmentioning

confidence: 99%

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High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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“…Indeed, SM and GM3 traffic within and between the plasma membrane and endosomes (46), whereas intracellular CE, normally found in lipid droplets, has also been detected in late endosomes (47). Of particular relevance, the accumulation of SM and gangliosides impairs lysosomal degradation of APP-CTFs, which enhances amyloidogenesis (48). A likely secondary implication of SM and GM3 accumulation is the propensity for ganglioside-enriched membrane microdomains at the cell surface and in endosomes to seed A␤ oligomerization (12).…”

Section: Discussionmentioning

confidence: 99%

Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

Chan

Oliveira

Cortés

et al. 2012

Journal of Biological Chemistry

496

505

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“…However, in contrast to ILEI, modifier of cell adhesion is a cytoplasmic protein that binds to presenilins on the cytoplasmic side of the membrane and destabilizes both APP-FL and APP-CTFs via an unknown mechanism 52 . Conversely, platelet-activating factor acetylhydrolase, isoform 1b, subunit 2 and sphingolipids inhibit g-secretase-independent degradation of APP-CTFs and increase Ab production 53,54 .…”

Section: Discussionmentioning

confidence: 99%

The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor

et al. 2014

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Accumulation of amyloid-b peptide (Ab) in the brain underlies the pathogenesis of Alzheimer's disease (AD). Ab is produced by b-and g-secretase-mediated sequential proteolysis of amyloid-b precursor protein (APP). Here we identify a secretory protein named interleukinlike epithelial-mesenchymal transition inducer (ILEI, also known as FAM3 superfamily member C) as a negative regulator of Ab production. ILEI destabilizes the b-secretasecleaved APP carboxy-terminal fragment, the penultimate precursor of Ab, by binding to the g-secretase complex and interfering with its chaperone properties. Notch signalling and g-secretase activity are not affected by ILEI. We also show neuronal expression of ILEI and its induction by transforming growth factor-b signalling. The level of secreted ILEI is markedly decreased in the brains of AD patients. Transgenic (Tg) overexpression of ILEI significantly reduces the brain Ab burden and ameliorates the memory deficit in AD model mice. ILEI may be a plausible target for the development of disease-modifying therapies.

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Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

Cited by 86 publications

References 78 publications

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor

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