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Cross-talk of membrane lipids and Alzheimer-related proteins.

Walter J, van Echten-Deckert G - Mol Neurodegener (2013)

Bottom Line: Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia.Notably, APP itself as well as the secretases are integral membrane proteins.Interestingly, APP and other AD associated proteins, including β-and γ-secretases can, in turn, influence lipid metabolic pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str, 25, 53127, Bonn, Germany. Jochen.Walter@ukb.uni-bonn.de.

ABSTRACT
Alzheimer's disease (AD) is neuropathologically characterized by the combined occurrence of extracellular β-amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the amyloid β-peptide (Aβ), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Aβ domain of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease complex involved in the generation of Aβ. Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia. The genetics of FAD together with biochemical and cell biological data, led to the formulation of the amyloid hypothesis, stating that accumulation and aggregation of Aβ is the primary event in the pathogenesis of AD, while tau might mediate its toxicity and neurodegeneration.The generation of Aβ involves sequential proteolytic cleavages of the amyloid precursor protein (APP) by enzymes called β-and γ-secretases. Notably, APP itself as well as the secretases are integral membrane proteins. Thus, it is very likely that membrane lipids are involved in the regulation of subcellular transport, activity, and metabolism of AD related proteins.Indeed, several studies indicate that membrane lipids, including cholesterol and sphingolipids (SLs) affect Aβ generation and aggregation. Interestingly, APP and other AD associated proteins, including β-and γ-secretases can, in turn, influence lipid metabolic pathways. Here, we review the close connection of cellular lipid metabolism and AD associated proteins and discuss potential mechanisms that could contribute to initiation and progression of AD.

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Lipid degradation and lysosomal lipid storage diseases. A) Sequential degradation pathways of selected (glyco)sphingolipids in which hydrolytic enzymes catalyzing SL degradation often need the assistance of an additional protein (GM2-activator or one of 3 saposins: SAP-B,-C,-D as indicated). B) Cholesterol storage in the late endosomal/lysosomal compartment due to mutated NPC1 or NPC2 proteins mediating its transport to post-lysosomal compartments (e.g. the ER). The names of respective diseases are indicated. Cer, Ceramide, Gal, D-galactose; GalNAc, N-Acetyl-D-galactosamine; Chol, cholesterol; Glc, D-glucose; GlcCer, glucosylceramide; LacCer, lactosylceramide; the terminology used for gangliosides GM1, GM2, GM3 is that of Svennerholm[106]; SM, sphingomyelin, Sph, sphingosine, Cerase, ceramidase; GlcCerase, Glucosylceramide-β-glucosidase; SMase, sphingomyelinase; SAP, sphingolipid activator protein, saposin. For detailed schemes on SL metabolism see[8].
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Figure 2: Lipid degradation and lysosomal lipid storage diseases. A) Sequential degradation pathways of selected (glyco)sphingolipids in which hydrolytic enzymes catalyzing SL degradation often need the assistance of an additional protein (GM2-activator or one of 3 saposins: SAP-B,-C,-D as indicated). B) Cholesterol storage in the late endosomal/lysosomal compartment due to mutated NPC1 or NPC2 proteins mediating its transport to post-lysosomal compartments (e.g. the ER). The names of respective diseases are indicated. Cer, Ceramide, Gal, D-galactose; GalNAc, N-Acetyl-D-galactosamine; Chol, cholesterol; Glc, D-glucose; GlcCer, glucosylceramide; LacCer, lactosylceramide; the terminology used for gangliosides GM1, GM2, GM3 is that of Svennerholm[106]; SM, sphingomyelin, Sph, sphingosine, Cerase, ceramidase; GlcCerase, Glucosylceramide-β-glucosidase; SMase, sphingomyelinase; SAP, sphingolipid activator protein, saposin. For detailed schemes on SL metabolism see[8].

Mentions: A number of studies showed that accumulation of SLs increased levels of APP and secretion of Aβ [32,95,98]. This was also observed in cellular and mouse models with impaired degradation of SLs that therefore resemble human LLSDs, including Niemann-Pick type A and B, Tay-Sachs and Sandhoff disease (Figure 2)[32,72,102]. The accumulation of lipids can impair lysosomal function and thereby lower the capacity of cells to degrade APP and its derivatives[32,103]. The genetic deletion of GD3 synthase and thereby inhibition of the biosynthesis of b-series gangliosides reduced Aβ deposition and improved memory deficits in APP transgenic mice[104]. Mice with deleted GM2 synthase gene that lack GM1, but have increased expression of GM3 showed more complex changes in Aβ deposition[105]. Interestingly, these mice developed in addition to a slight increase in Aβ plaque load in the parenchyma, also prominent vascular amyloid angiopathy[105]. Thus, gangliosides might not only affect the general deposition, but also influence the region specific formation of Aβ aggregates.


Cross-talk of membrane lipids and Alzheimer-related proteins.

Walter J, van Echten-Deckert G - Mol Neurodegener (2013)

Lipid degradation and lysosomal lipid storage diseases. A) Sequential degradation pathways of selected (glyco)sphingolipids in which hydrolytic enzymes catalyzing SL degradation often need the assistance of an additional protein (GM2-activator or one of 3 saposins: SAP-B,-C,-D as indicated). B) Cholesterol storage in the late endosomal/lysosomal compartment due to mutated NPC1 or NPC2 proteins mediating its transport to post-lysosomal compartments (e.g. the ER). The names of respective diseases are indicated. Cer, Ceramide, Gal, D-galactose; GalNAc, N-Acetyl-D-galactosamine; Chol, cholesterol; Glc, D-glucose; GlcCer, glucosylceramide; LacCer, lactosylceramide; the terminology used for gangliosides GM1, GM2, GM3 is that of Svennerholm[106]; SM, sphingomyelin, Sph, sphingosine, Cerase, ceramidase; GlcCerase, Glucosylceramide-β-glucosidase; SMase, sphingomyelinase; SAP, sphingolipid activator protein, saposin. For detailed schemes on SL metabolism see[8].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016522&req=5

Figure 2: Lipid degradation and lysosomal lipid storage diseases. A) Sequential degradation pathways of selected (glyco)sphingolipids in which hydrolytic enzymes catalyzing SL degradation often need the assistance of an additional protein (GM2-activator or one of 3 saposins: SAP-B,-C,-D as indicated). B) Cholesterol storage in the late endosomal/lysosomal compartment due to mutated NPC1 or NPC2 proteins mediating its transport to post-lysosomal compartments (e.g. the ER). The names of respective diseases are indicated. Cer, Ceramide, Gal, D-galactose; GalNAc, N-Acetyl-D-galactosamine; Chol, cholesterol; Glc, D-glucose; GlcCer, glucosylceramide; LacCer, lactosylceramide; the terminology used for gangliosides GM1, GM2, GM3 is that of Svennerholm[106]; SM, sphingomyelin, Sph, sphingosine, Cerase, ceramidase; GlcCerase, Glucosylceramide-β-glucosidase; SMase, sphingomyelinase; SAP, sphingolipid activator protein, saposin. For detailed schemes on SL metabolism see[8].
Mentions: A number of studies showed that accumulation of SLs increased levels of APP and secretion of Aβ [32,95,98]. This was also observed in cellular and mouse models with impaired degradation of SLs that therefore resemble human LLSDs, including Niemann-Pick type A and B, Tay-Sachs and Sandhoff disease (Figure 2)[32,72,102]. The accumulation of lipids can impair lysosomal function and thereby lower the capacity of cells to degrade APP and its derivatives[32,103]. The genetic deletion of GD3 synthase and thereby inhibition of the biosynthesis of b-series gangliosides reduced Aβ deposition and improved memory deficits in APP transgenic mice[104]. Mice with deleted GM2 synthase gene that lack GM1, but have increased expression of GM3 showed more complex changes in Aβ deposition[105]. Interestingly, these mice developed in addition to a slight increase in Aβ plaque load in the parenchyma, also prominent vascular amyloid angiopathy[105]. Thus, gangliosides might not only affect the general deposition, but also influence the region specific formation of Aβ aggregates.

Bottom Line: Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia.Notably, APP itself as well as the secretases are integral membrane proteins.Interestingly, APP and other AD associated proteins, including β-and γ-secretases can, in turn, influence lipid metabolic pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str, 25, 53127, Bonn, Germany. Jochen.Walter@ukb.uni-bonn.de.

ABSTRACT
Alzheimer's disease (AD) is neuropathologically characterized by the combined occurrence of extracellular β-amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the amyloid β-peptide (Aβ), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Aβ domain of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease complex involved in the generation of Aβ. Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia. The genetics of FAD together with biochemical and cell biological data, led to the formulation of the amyloid hypothesis, stating that accumulation and aggregation of Aβ is the primary event in the pathogenesis of AD, while tau might mediate its toxicity and neurodegeneration.The generation of Aβ involves sequential proteolytic cleavages of the amyloid precursor protein (APP) by enzymes called β-and γ-secretases. Notably, APP itself as well as the secretases are integral membrane proteins. Thus, it is very likely that membrane lipids are involved in the regulation of subcellular transport, activity, and metabolism of AD related proteins.Indeed, several studies indicate that membrane lipids, including cholesterol and sphingolipids (SLs) affect Aβ generation and aggregation. Interestingly, APP and other AD associated proteins, including β-and γ-secretases can, in turn, influence lipid metabolic pathways. Here, we review the close connection of cellular lipid metabolism and AD associated proteins and discuss potential mechanisms that could contribute to initiation and progression of AD.

Show MeSH
Related in: MedlinePlus