Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Tamboli, Irfan Y.; Prager, Kai; Thal, Dietmar Rudolf; Thelen, Karin; Dewachter, Ilse; Pietrzik, Claus U.; George-Hyslop, Peter St; Sisodia, Sangram S.; Strooper, Bart De; Heneka, Michael T.; Филиппов, М. А.; Müller, Ulrike; Leuven, Freddy Van; Lütjohann, Dieter; Walter, Jochen

doi:10.1523/jneurosci.2635-08.2008

Cited by 67 publications

(78 citation statements)

References 75 publications

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“…Immunocytochemistry-Cells were processed for immunocytochemistry as described previously (28). Briefly, cells were cultured on poly-L-lysine-coated coverslips and fixed with 4% paraformaldehyde for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, ␣-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-␤ peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.Alzheimer disease is characterized by the accumulation of extracellular amyloid plaques that contain aggregates of the amyloid ␤-peptide (A␤).5 A␤ is derived from the amyloid precursor protein by sequential proteolytic processing by ␤-and ␥-secretases (1, 2). The initial cleavage of amyloid precursor protein (APP) by ␤-secretase results in the secretion of the soluble ectodomain and the generation of a membrane-tethered C-terminal fragment (APP-CTF␤). Subsequently, APP-CTF␤ can be cleaved by ␥-secretase to liberate A␤ from cellular membranes (2). In an alternative pathway, APP can also be cleaved by ␣-secretase within the A␤ domain, thereby generating CTF␣. The subsequent cleavage of APP-CTF␣ by ␥-secretase results in secretion of a small peptide called p3 (2). It is important to note that APP is also metabolized by additional pathways, including proteasomal and lysosomal degradation (3-5).The metabolism of APP is also regulated by macroautophagy (herein referred to as autophagy), a lysosome-dependent degradative pathway for long lived proteins, organelles, and nutrient recycling (6, 7). Autophagy starts with the formation of double-membrane vesicles, the so-called autophagosomes, which further fuse with lysosomes to become autolysosomes for degradation of autophagosome contents by lysosomal hydrolases (8). Autophagy is an essential prosurvival pathway induced by a variety of stress factors, including nutrient deprivation, growth factor withdrawal, oxidative stress, infection, and hypoxia (9). These factors contribute to the etiology of multiple diseases such as cancer, stroke, heart disease, and infection (10). Eukaryotic cells have a basal autophagic activity under normal physiological conditions. Cells deficient in autophagy show diffuse abnormal protein accumulation and mitochondrial disorganization (11,12), suggesting that autophagy is important to maintain cellular homeostasis by eliminating protein aggregates and damaged organelles. Basal ...

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Section: Methodsmentioning

confidence: 99%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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“…Clones were selected with 100 g/ml zeocine (Invitrogen). For immunocytochemistry, cells grown on polylysine-coated glass coverslips were fixed in 4% paraformaldehyde before processing for immunofluorescence as described previously (Tamboli et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

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

Tamboli¹,

Hampel²,

Tiên³

et al. 2011

J. Neurosci.

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“…These mutations may exert additional effects on cellular signaling as a consequence of the altered processing of certain membrane proteins that could influence lipid cellular homeostasis. Interestingly, γ-secretase loss of function induced by the ablation of PSs or by transgenic expression of PS1 mutants provoked a severe imbalance in the cholesterol content of the plasma membrane and intracellular membranes [33,34]. In this sense, PS ablation increased the overall levels of cholesterol and sphingomyelin (SM) in cells, whereas the local concentration of cholesterol at the plasma membrane was dramatically reduced, resulting in the intracellular accumulation of cholesterol and cholesterol-rich membrane domains, such as lipid rafts [33,34].…”

Section: Cholesterol and Sphingolipid Homeostasis In Admentioning

confidence: 99%

“…Furthermore, individuals carrying the ApoE4 allele accumulate less ApoE lipoprotein in the brain than non-ApoE4 carriers [38]. Hence, the expression of ApoE4 in SAD cases appears to alter cholesterol homeostasis in neurons in a similar way as that induced by γ-secretase loss-of-function in PS1-deficient cells and transgenic models of AD harboring clinical PS1 mutations [33,34]. In such AD models, the loss of γ-secretase activity leads to impaired uptake of lipoproteins from the extracellular media due to the poor internalization of ApoE receptors like the LDLR (low-density lipoprotein receptor) [34].…”

Section: Cholesterol and Sphingolipid Homeostasis In Admentioning

confidence: 99%

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

Torres¹,

Busquets²,

Escribá³

2016

Update on Dementia

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Alzheimer's disease (AD) is a neurodegenerative disorder that causes severe and progressive cognitive impairment. The discovery of specific mutations related to AD supported the amyloid cascade hypothesis, which postulates that the accumulation of the amyloid-β (Aβ) peptide triggers neuronal death and dementia. However, most drugs that aim to prevent Aβ accumulation or tau phosphorylation have consistently failed in clinical trials. This would suggest that the amyloid pathology lies downstream of (an)other cellular event(s) that is/are responsible for AD pathogenesis. In this context, several lipid alterations have been described in the brain and in peripheral fluids of patients with AD, suggesting the involvement of lipids in the etiology of this condition. Indeed, the central nervous system (CNS) has the highest lipid content in the body, next to adipose tissue, and it is thought that normalization of brain membrane lipid levels would revert AD-related pathogenic events. In this sense, novel hydroxylated derivatives of docosahexaenoic acid (DHA) such as natural resolvins or synthetic hydroxy-DHA (HDHA, DHALifort) can modulate membrane lipid composition and show remarkable beneficial effects on AD hallmarks, such as prevention of amyloid production and tau phosphorylation, and cognitive restoration in animal models. Therefore, normalization of the neuronal lipid environment by hydroxyl-DHA and/or other lipids may constitute a promising therapy for AD treatment, memory loss and, possibly, other types of dementia.

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Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Cited by 67 publications

References 75 publications

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

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

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

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