GM1 ganglioside regulates the proteolysis of amyloid precursor protein

Zha, Qinqin; Ruan, Yan; Hartmann, Tobias; Beyreuther, Konrad; Zhang, D

doi:10.1038/sj.mp.4001509

Cited by 96 publications

(90 citation statements)

References 42 publications

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“…2B). In support of this view, exogenous addition of GM1 in cultured neurons enhances A production in parallel with inhibition of sAPPsecretion (Zha et al, 2004). These results suggest that GM1 regulates processing of APP by regulating the activity of secretases.…”

Section: Regulatory Roles Of Gangliosides On App Processingsupporting

confidence: 61%

“…These results suggest that GM1 regulates processing of APP by regulating the activity of secretases. There are two potential mechanisms for the inhibition of -secretase cleavage by GM1 (Zha et al, 2004). First, stiffening of the membrane due to GM1 loading may decrease sAPP by inhibiting lateral movement and preventing the required contact between the enzyme and substrate.…”

Section: Regulatory Roles Of Gangliosides On App Processingmentioning

confidence: 99%

See 1 more Smart Citation

Gangliosides as a Double-Edged Swordin Neurodegenerative Disease

Sekigawa¹,

Fujita²,

Sekiyama³

et al. 2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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Section: Regulatory Roles Of Gangliosides On App Processingsupporting

confidence: 61%

Section: Regulatory Roles Of Gangliosides On App Processingmentioning

confidence: 99%

Gangliosides as a Double-Edged Swordin Neurodegenerative Disease

Sekigawa¹,

Fujita²,

Sekiyama³

et al. 2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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“…Increasing evidence indicates that sialic acid containing gangliosides are pivotal in the mechanism of Aβ binding to cells [7,[22][23][24][25][26][27]. Aβ has higher affinity for gangliosides which are clustered and gangliosides containing multiple sialic acids, than it does for other glycolipids [9,[28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

2008

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Abstractβ-Amyloid peptide (Aβ), the primary protein component in senile plaques associated with Alzheimer's disease (AD), has been implicated in neurotoxicity associated with AD. Previous studies have shown that the Aβ-neuronal membrane interaction plays a crucial role in Aβ toxicity. More specifically, it is thought that Aβ interacts with ganglioside rich and sialic acid rich regions of cell surfaces. In light of such evidence, we have hypothesized that the Aβ-membrane sialic acid interaction could be inhibited through use of a biomimic multivalent sialic acid compound that would compete with the cell surface for Aβ binding. To explore this hypothesis, we synthesized a series of photocrosslinked sialic acid containing oligosaccharides and tested their ability to bind Aβ and attenuate Aβ toxicity in cell culture assays. We show that a polymer prepared via the photocrosslinking of disialyllacto-N-tetraose (DSLNT) was able to attenuate Aβ toxicity at low micromolar concentrations without adversely affecting the cell viability. Polymers prepared from mono-sialyl-oligosaccharides were less effective at Aβ toxicity attenuation. These results demonstrate the feasibility of using photocrosslinked sialyl-oligosaccharides for prevention of Aβ toxicity in vitro and may provide insight into the design of new materials for use in attenuation of Aβ toxicity associated with AD.

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“…Aβ production [80][81][82][83] . In addition, inhibition of 3-hydroxy-3-methylglutaryl-CoA-reductase and 7-dehydro-cholesterolreductase [84] , both key enzymes in cholesterol synthesis, reduces both intracellular and extracellular Aβ levels [80,81] .…”

Section: Role Of Cholesterol Metabolism In Ad Pathogenesismentioning

confidence: 99%

“…Cholesterol alters Aβ production by regulating secretase activity [23] . Reducing the membrane cholesterol levels can also decrease the activity of BACE1 and γ-secretase, and lead to reducedAβ production [80][81][82][83] . In addition, inhibition of 3-hydroxy-3-methylglutaryl-CoA-reductase and 7-dehydro-cholesterolreductase [84] , both key enzymes in cholesterol synthesis, reduces both intracellular and extracellular Aβ levels [80,81] .…”

mentioning

confidence: 99%

Lipid metabolism in Alzheimer’s disease

Liu

Zhang

2014

Neurosci. Bull.

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Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis. Keywords: brain aging; lipid metabolism; Alzheimer's disease ·Review· IntroductionLipids are abundant in the brain. These lipids consist of glycerophospholipids (GPs), sphingolipids, and cholesterol in roughly equimolar proportions [1] . The brain contains about 20% of the total body cholesterol [2] . Cholesterol is primarily derived from local synthesis, whereas uptake of lipoprotein particle-derived cholesterol from the peripheral circulation is usually prevented by the blood-brain-barrier. Lipids, especially cholesterol, have recently been extensively studied in many neurodegenerative diseases. Impairment of cholesterol metabolism (synthesis, transport, and utilization by neurons) in the brain is linked to Alzheimer's disease (AD) and the aging process. In addition, lipid oxidation products accumulate at high levels in aging tissues in mice [3] . Recent studies have demonstrated the important role of altered metabolism in AD [4] . Sphingomyelinases promote apoptosis in human primary neurons through the generation of a proapoptotic molecule, ceramide [5] .Moreover, upregulated arachidonic acid metabolism has been reported in hAPP-J20 AD mice as well as in the AD brain, particularly in regions having high densities of senile plaques with activated microglia [6,7] . Although the potential link between cholesterol and AD pathogenesis has been intensively studied, growing evidence suggests that other lipids, such as sphingolipids and GPs, also play an important role. Here, we review some recent advances in understanding the role lipids play in the aging process and AD pathogenesis. Major Lipid Classes and Functions in the BrainAlthough most lipids serve as structural lipids in cell membranes, they are also directly involved in membrane trafficking, intracellular architecture, and the regulation of proteins and sub-compartments in membranes (lipid rafts) (Table 1). Eukaryotic organisms might contain a dozen major lipid classes, each comprising hundreds of individual molecular species [8] . Lipids have the potential to generate 9 000-100 000 molecular species [9,10] , and a mammalian cell may contain 1 000-2 000 [11] . The brain is one of the most lipid-enriched organs, containing several major classes, such as cholesterol, GPs, sphingolipids and fatty acids [12] . The biological significance of the compositional complexity of lipids is poorly understood. However, the recent development of the shot-gun lipidomics technique may provide more sensitive and quant...

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GM1 ganglioside regulates the proteolysis of amyloid precursor protein

Cited by 96 publications

References 42 publications

Gangliosides as a Double-Edged Swordin Neurodegenerative Disease

Gangliosides as a Double-Edged Swordin Neurodegenerative Disease

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

Lipid metabolism in Alzheimer’s disease

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