Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Wang, Steven S.‐S.; Rymer, Dawn L.; Good, Theresa A.

doi:10.1074/jbc.m102834200

Cited by 96 publications

(100 citation statements)

References 96 publications

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“…2A). The compactin-treatment was reported to reduce the cellular cholesterol level to about 40% of the normal level without affecting the viability [19] and we have found that inhibiting the synthesis of cholesterol reduced ganglioside content [13]. According to the decrease in ganglioside and cholesterol contents, the accumulation of hIAPP amyloids was significantly suppressed (Fig.…”

Section: Resultsmentioning

confidence: 76%

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Wakabayashi¹,

Matsuzaki²

2009

FEBS Letters

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Edited by Jesus Avila Keywords:Human islet amyloid polypeptide Amyloid fibril Ganglioside Cholesterol Lipid raft a b s t r a c t Human islet amyloid polypeptide (hIAPP) is the primary component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. However, it is unknown how amyloid fibrils are formed in vivo. In this study, we demonstrate that gangliosides play an essential role in the formation of amyloid deposits by hIAPP on plasma membranes. Amyloid fibrils accumulated in ganglioside-and cholesterol-rich microscopic domains ('lipid rafts'). The depletion of gangliosides or cholesterol significantly reduced the amount of amyloid deposited. These results clearly showed that the formation of amyloid fibrils was mediated by gangliosides in lipid rafts.

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Section: Resultsmentioning

confidence: 76%

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Wakabayashi¹,

Matsuzaki²

2009

FEBS Letters

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“…Lyophilized Aβ40 and Aβ42 of greater than 95% purity were obtained from American Peptide (Sunnyvale, CA) or rPeptide (Athens, GA). H13A and H14A variants of Aβ42 were obtained from rPeptide, while Aβ 1-28 , Aβ [22][23][24][25][26][27][28][29][30][31][32][33][34][35] , α-MSH, and neurotensin were obtained from American Peptide. The Aβ42 mutant M35V (21) as well as Aβ42 with an oxidized methionine (M35 OX ) (20) were kindly provided by Dr. Kevin Barnham.…”

Section: Methodsmentioning

confidence: 99%

“…When DA was used as the oxidizable substrate instead of SAPC, it was also oxidized extensively by Cu(II) and H 2 O 2 over 120 min ( Figure 4C). Aβ42, Aβ 1-28 , and Aβ [22][23][24][25][26][27][28][29][30][31][32][33][34][35] inhibited DA oxidation but not the control peptides α-MSH and neurotensin. We conclude that Aβ peptides specifically inhibit oxidation of substrates such as SAPC and DA under these conditions.…”

Section: Antioxidant Activity Of Aβ42mentioning

confidence: 99%

“…by Aβ proteins mediates neurotoxicity (20)(21)(22), that merely altering membrane lipid composition protects PC12 cells from Aβ-mediated toxicity (23), and that plasma membranes from human brain are particularly effective at accelerating Aβ fibrillogenesis (24). Thus, it is important to understand the nature of the interaction between Aβ proteins and lipid membranes, particularly membranes subject to oxidative damage.…”

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confidence: 99%

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Promotion of Oxidative Lipid Membrane Damage by Amyloid β Proteins

2005

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Senile plaques in the cerebral parenchyma are a pathognomonic feature of Alzheimer's disease (AD) and are mainly composed of aggregated fibrillar amyloid β (Aβ) proteins. The plaques are associated with neuronal degeneration, lipid membrane abnormalities, and chemical evidence of oxidative stress. The view that Aβ proteins cause these pathological changes has been challenged by suggestions that they have a protective function or that they are merely byproducts of the pathological process. This investigation was conducted to determine whether Aβ proteins promote or inhibit oxidative damage to lipid membranes. Using a mass spectrometric assay of oxidative lipid damage, the 42-residue form of Aβ (Aβ42) was found to accelerate the oxidative lipid damage caused by physiological concentrations of ascorbate and submicromolar concentrations of copper(II) ion. Under these conditions, Aβ42 was aggregated, but nonfibrillar. Ascorbate and copper produced H 2 O 2 , but Aβ42 reduced H 2 O 2 concentrations, and its ability to accelerate oxidative damage was not affected by catalase. Lipids could be oxidized by H 2 O 2 and copper-(II) in the absence of ascorbate, but only at significantly higher concentrations, and Aβ42 inhibited this reaction. These results indicate that the ability of Aβ42 to promote oxidative damage is more potent and more likely to be manifest in vivo than its ability to inhibit oxidative damage. In conjunction with prior results demonstrating that oxidatively damaged membranes cause Aβ42 to misfold and form fibrils, these results suggest a specific chemical mechanism linking Aβ42-promoted oxidative lipid damage to amyloid fibril formation.

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“…Alzheimer's disease can only be diagnosed definitively by identifying extracellular amyloid plaques composed of amyloid-β (Aβ) and neurofibrillary tangles, which consist of tau proteins, in postmortem central nervous system tissue [5,[23][24][25][26][27][28][29][30]. The main constituent of the neuritic plaques is the 39-43 amino acid peptide, β-amyloid (Aβ).…”

Section: Introductionmentioning

confidence: 99%

Application of Surface-Enhanced Raman Spectroscopy for Detection of Beta Amyloid Using Nanoshells

et al. 2007

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Currently, no methods exist for the definitive diagnosis of AD premortem. β-amyloid, the primary component of the senile plaques found in patients with this disease, is believed to play a role in its neurotoxicity. We are developing a nanoshell substrate, functionalized with sialic acid residues to mimic neuron cell surfaces, for the surface-enhanced Raman detection of β-amyloid. It is our hope that this sensing mechanism will be able to detect the toxic form of β-amyloid, with structural and concentration information, to aid in the diagnosis of AD and provide insight into the relationship between β-amyloid and disease progression. We have been successfully able to functionalize the nanoshells with the sialic acid residues to allow for the specific binding of β-amyloid to the substrate. We have also shown that a surface-enhanced Raman spectroscopy response using nanoshells is stable and concentrationdependent with detection into the picomolar range.

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Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Cited by 96 publications

References 96 publications

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

Promotion of Oxidative Lipid Membrane Damage by Amyloid β Proteins

Application of Surface-Enhanced Raman Spectroscopy for Detection of Beta Amyloid Using Nanoshells

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