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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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Cross-talk of membrane lipids and Alzheimer-associated proteins. Alterations in membrane lipid composition affect secretase activities, thereby modulating APP processing and generation of Aβ. Alternatively, membrane lipids can directly interact with Aβ and modulate its aggregation. In addition, membrane lipids impair the metabolism of tau. Thus, both neuropathological hallmarks of AD could be triggered by age-dependent changes in lipid metabolism. Conversely, membrane lipid composition is affected by APP and its derivatives Aβ and CTFβ, which were shown to modulate lipid metabolic enzymes and directly bind membrane lipids including cholesterol and gangliosides. Tau also affects membrane lipid composition, likely via regulation of vesicular transport. ApoE as a major lipoprotein in the brain could also affect lipid composition, but also Aβ clearance and aggregation. Solid arrows indicate a direct interaction of the respective components whereas dotted arrows indicate potential modulations by yet undefined mechanisms. See text for further details.
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Figure 3: Cross-talk of membrane lipids and Alzheimer-associated proteins. Alterations in membrane lipid composition affect secretase activities, thereby modulating APP processing and generation of Aβ. Alternatively, membrane lipids can directly interact with Aβ and modulate its aggregation. In addition, membrane lipids impair the metabolism of tau. Thus, both neuropathological hallmarks of AD could be triggered by age-dependent changes in lipid metabolism. Conversely, membrane lipid composition is affected by APP and its derivatives Aβ and CTFβ, which were shown to modulate lipid metabolic enzymes and directly bind membrane lipids including cholesterol and gangliosides. Tau also affects membrane lipid composition, likely via regulation of vesicular transport. ApoE as a major lipoprotein in the brain could also affect lipid composition, but also Aβ clearance and aggregation. Solid arrows indicate a direct interaction of the respective components whereas dotted arrows indicate potential modulations by yet undefined mechanisms. See text for further details.

Mentions: APP and its derivatives generated by γ-secretase can contribute to the regulation of lipid metabolic pathways (Figure 3). Aβ itself can alter the activity of enzymes involved in sphingolipid and cholesterol metabolism. Aβ42 increased the activity of neutral SMase and thereby decreased SM levels in cultured cells, while Aβ40 inhibited HMG-CoA reductase and lead to decreased cholesterol biosynthesis[128]. Alternatively, Aβ-dependent increases in ceramide and cholesterol levels might be mediated by membrane-associated oxidative stress[129-131]. In line with the effect of FAD associated mutations in PS proteins on Aβ42/40 ratios, expression of FAD mutant PS1 increased cholesterol levels, but decreased SM levels. Increased cholesterol levels were also observed in cells from PS KO mice and in brains of mice expressing FAD-mutant PS1[132,133]. However, the studies proposed alternative mechanisms underlying the changes in cellular cholesterol levels. The γ-secretase cleavage product AICD could act as a transcriptional regulator of the LDL receptor related protein 1(LRP1). As AICD negatively regulates LRP1 transcription, LRP1 protein expression was increased in PS1 deficient cells where AICD production by γ-secretase is inhibited. Thus, extracellular cholesterol complexed with apoE could be internalized more efficiently in PS deficient cells thereby increasing cellular cholesterol levels[132]. However, own work demonstrated that the uptake of lipoproteins is rather decreased in PS deficient FAD mutant cells and mouse brain[133]. The deficit in the internalization of extracellular cholesterol in turn upregulated cholesterol biosynthetic genes including SREBP2 and CYP51, resulting in an overproduction of cholesterol[133]. A recent study demonstrated that a significant pool of PS protein is localized in membrane-associated mitochondria (MAM), sites with close contacts of mitochondrial and ER membranes[134,135]. MAM structures were increased in PS KO or PS1 FAD mutant cells, suggesting that PS proteins and associated γ-secretase activity negatively regulated MAM contacts. PS deficient cells also showed increased biosynthesis of cholesterol[135]. Interestingly, MAMs appear to be important for the generation of cholesterol esters and their storage in lipid droplets. In line with an increased number and size of MAMs, cholesterol esters and lipid droplets were found to be significantly increased in PS deficient cells. While further studies are required to dissect the molecular pathways, it is evident that γ-secretase activity is closely related to cellular cholesterol metabolism.


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

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

Cross-talk of membrane lipids and Alzheimer-associated proteins. Alterations in membrane lipid composition affect secretase activities, thereby modulating APP processing and generation of Aβ. Alternatively, membrane lipids can directly interact with Aβ and modulate its aggregation. In addition, membrane lipids impair the metabolism of tau. Thus, both neuropathological hallmarks of AD could be triggered by age-dependent changes in lipid metabolism. Conversely, membrane lipid composition is affected by APP and its derivatives Aβ and CTFβ, which were shown to modulate lipid metabolic enzymes and directly bind membrane lipids including cholesterol and gangliosides. Tau also affects membrane lipid composition, likely via regulation of vesicular transport. ApoE as a major lipoprotein in the brain could also affect lipid composition, but also Aβ clearance and aggregation. Solid arrows indicate a direct interaction of the respective components whereas dotted arrows indicate potential modulations by yet undefined mechanisms. See text for further details.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Cross-talk of membrane lipids and Alzheimer-associated proteins. Alterations in membrane lipid composition affect secretase activities, thereby modulating APP processing and generation of Aβ. Alternatively, membrane lipids can directly interact with Aβ and modulate its aggregation. In addition, membrane lipids impair the metabolism of tau. Thus, both neuropathological hallmarks of AD could be triggered by age-dependent changes in lipid metabolism. Conversely, membrane lipid composition is affected by APP and its derivatives Aβ and CTFβ, which were shown to modulate lipid metabolic enzymes and directly bind membrane lipids including cholesterol and gangliosides. Tau also affects membrane lipid composition, likely via regulation of vesicular transport. ApoE as a major lipoprotein in the brain could also affect lipid composition, but also Aβ clearance and aggregation. Solid arrows indicate a direct interaction of the respective components whereas dotted arrows indicate potential modulations by yet undefined mechanisms. See text for further details.
Mentions: APP and its derivatives generated by γ-secretase can contribute to the regulation of lipid metabolic pathways (Figure 3). Aβ itself can alter the activity of enzymes involved in sphingolipid and cholesterol metabolism. Aβ42 increased the activity of neutral SMase and thereby decreased SM levels in cultured cells, while Aβ40 inhibited HMG-CoA reductase and lead to decreased cholesterol biosynthesis[128]. Alternatively, Aβ-dependent increases in ceramide and cholesterol levels might be mediated by membrane-associated oxidative stress[129-131]. In line with the effect of FAD associated mutations in PS proteins on Aβ42/40 ratios, expression of FAD mutant PS1 increased cholesterol levels, but decreased SM levels. Increased cholesterol levels were also observed in cells from PS KO mice and in brains of mice expressing FAD-mutant PS1[132,133]. However, the studies proposed alternative mechanisms underlying the changes in cellular cholesterol levels. The γ-secretase cleavage product AICD could act as a transcriptional regulator of the LDL receptor related protein 1(LRP1). As AICD negatively regulates LRP1 transcription, LRP1 protein expression was increased in PS1 deficient cells where AICD production by γ-secretase is inhibited. Thus, extracellular cholesterol complexed with apoE could be internalized more efficiently in PS deficient cells thereby increasing cellular cholesterol levels[132]. However, own work demonstrated that the uptake of lipoproteins is rather decreased in PS deficient FAD mutant cells and mouse brain[133]. The deficit in the internalization of extracellular cholesterol in turn upregulated cholesterol biosynthetic genes including SREBP2 and CYP51, resulting in an overproduction of cholesterol[133]. A recent study demonstrated that a significant pool of PS protein is localized in membrane-associated mitochondria (MAM), sites with close contacts of mitochondrial and ER membranes[134,135]. MAM structures were increased in PS KO or PS1 FAD mutant cells, suggesting that PS proteins and associated γ-secretase activity negatively regulated MAM contacts. PS deficient cells also showed increased biosynthesis of cholesterol[135]. Interestingly, MAMs appear to be important for the generation of cholesterol esters and their storage in lipid droplets. In line with an increased number and size of MAMs, cholesterol esters and lipid droplets were found to be significantly increased in PS deficient cells. While further studies are required to dissect the molecular pathways, it is evident that γ-secretase activity is closely related to cellular cholesterol metabolism.

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