Lipid Binding to Amyloid β‐Peptide Aggregates: Preferential Binding of Cholesterol as Compared with Phosphatidylcholine and Fatty Acids

Avdulov, N. A.; Chochina, Svetlana V.; Igbavboa, Urule; Warden, Christopher S.; Vassiliev, Alexei V.; Wood, W. Gibson

doi:10.1046/j.1471-4159.1997.69041746.x

Cited by 172 publications

(134 citation statements)

References 21 publications

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“…It has been demonstrated that amyloid fibril formation can be induced by A␤ binding to membrane vesicles containing gangliosides (47) and vesicles reconstituted from acidic and negatively charged phospholipids (48,49). We recently reported that A␤ aggregates bind fluorescent-labeled cholesterol, phosphatidylcholine, and stearic acid (50). The affinity of cholesterol for aggregated A␤ was significantly higher as compared with other lipids that were examined.…”

Section: Discussionmentioning

confidence: 96%

“…Thus, membrane cholesterol may act as an anchor for polymers of A␤ . It was observed that significant binding of cholesterol to A␤ occurred after polymers were formed and that membranes enriched in cholesterol may be more susceptible to deposition of A␤ (50). For example, the exofacial or outer leaflet of SPM from aged mice contains more than twice the amount of cholesterol present in the exofacial leaflet of SPM from young mice (20).…”

Section: Discussionmentioning

confidence: 99%

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Distribution and Fluidizing Action of Soluble and Aggregated Amyloid β-Peptide in Rat Synaptic Plasma Membranes

Mason

Jacob

Walter

et al. 1999

Journal of Biological Chemistry

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127

110

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The effects of soluble and aggregated amyloid ␤-peptide (A␤) on cortical synaptic plasma membrane (SPM) structure were examined using small angle x-ray diffraction and fluorescence spectroscopy approaches. Electron density profiles generated from the x-ray diffraction data demonstrated that soluble and aggregated A␤ 1-40 peptides associated with distinct regions of the SPM. The width of the SPM samples, including surface hydration, was 84 Å at 10°C. Following addition of soluble A␤ 1-40 , there was a broad increase in electron density in the SPM hydrocarbon core ؎0 -15 Å from the membrane center, and a reduction in hydrocarbon core width by 6 Å. By contrast, aggregated A␤ 1-40 contributed electron density to the phospholipid headgroup/hydrated surface of the SPM ؎24 -37 Å from the membrane center, concomitant with an increase in molecular volume in the hydrocarbon core. The SPM interactions observed for A␤ 1-40 were reproduced in a brain lipid membrane system. In contrast to A␤ 1-40 , aggregated A␤ 1-42 intercalated into the lipid bilayer hydrocarbon core ؎0 -12 Å from the membrane center. Fluorescence experiments showed that both soluble and aggregated A␤ 1-40 significantly increased SPM bulk and protein annular fluidity. Physico-chemical interactions of A␤ with the neuronal membrane may contribute to mechanisms of neurotoxicity, independent of specific receptor binding. Alzheimer's disease (AD)1 is a progressive neurodegenerative disorder characterized by the accumulation of neuritic plaques composed of amyloid ␤-peptide (A␤) variants, extracellular matrix components, and apolipoproteins (1, 2). A␤ is an amphipathic, 39 -42-residue peptide that is derived by proteolytic cleavage of the transmembrane glycoprotein, the amyloid precursor protein; the A␤ domain is composed of 28 extracellular and 12-14 transmembrane amino acid residues of amyloid precursor protein (3). An increase in the production and abnormal accumulation of A␤ in the brain has been implicated in the etiology of AD. Several studies have shown that A␤ analogs can directly disrupt neuronal function, contributing to cell death associated with the development of AD (4 -8).It has been postulated that the biological activity of A␤ is related to its ability to form insoluble aggregates in solution (9 -11), although the cellular mechanism of action is not well understood. A recent study from Cotman and co-workers (12) showed that A␤ neurotoxicity is independent of stereoisomerspecific ligand-receptor interaction because both all-D-and all-L-stereoisomers of A␤ [25][26][27][28][29][30][31][32][33][34][35] and A␤ 1-40 had similar neurotoxic activity. This finding suggests that A␤ modulates membrane function by a nonreceptor-mediated mechanism, potentially as a result of altering the physico-chemical properties of membrane constituents, including lipids and proteins (13-16). Indeed, previous membrane equilibrium binding experiments have demonstrated that the A␤ 25-35 fragment is highly lipophilic (K P Ͼ 10 2 ); the peptide intercalates deep into the membra...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Distribution and Fluidizing Action of Soluble and Aggregated Amyloid β-Peptide in Rat Synaptic Plasma Membranes

Mason

Jacob

Walter

et al. 1999

Journal of Biological Chemistry

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127

110

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“…It is possible that APP in DIGs is rapidly processed such that the steady-state levels of this protein are lower than would otherwise be expected. Another possibility is that, as the Aβ peptide has a high affinity for cholesterol [46] and ganglioside G M" [47][48][49], both of which are enriched in DIGs [8,25], this peptide rapidly translocates to DIGs after it is cleaved from APP. Finally, although depleting cells of cholesterol with methyl-β-cyclodextrin has been shown to decrease the production of Aβ [37], this effect may not be entirely due to disruption of lipid rafts, as such treatment has also been shown to disrupt clathrincoated pits [50] in which APP has been localized [51].…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein

Parkin

Turner

Hooper

1999

Biochemical Journal

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Lipid rafts are regions of the plasma membrane that are enriched in cholesterol, glycosphingolipids and acylated proteins, and which have been proposed as sites for the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Lipid rafts can be isolated on the basis of their insolubility in Triton X-100 at 4 mC, with the resulting low-density, detergent-insoluble glycolipid-enriched fraction (DIG) being isolated by flotation through a sucrose density gradient. The detergent-insolubility of APP in mouse cerebral cortex relative to a variety of DIG marker proteins (alkaline phosphatase, flotillin, F3 protein and prion protein) and non-DIG proteins (alkaline phosphodiesterase I, aminopeptidase A and clathrin) has been examined. Alkaline phosphatase, flotillin, F3 protein and the prion protein were present exclusively in the DIG region of the sucrose gradient over a range of protein\detergent ratios used to solubilize the membranes and displayed a characteristic enrichment in the lowdensity fraction as the protein\detergent ratio was decreased. In

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“…In contrast, the high threshold, predominantly presynaptic P/Q-type channels (15-17 pS) are suppressed by A␤ oligomers (50), which serves to reduce synaptic vesicle release, neurotransmission, and plasticity. Disruption of Membrane Lipid Integrity-A␤ peptides interact with membrane lipids such as phosphoinositides (51), phosphatidylglycerol (52), phosphatidylcholine (53), and gangliosides (54). A direct interaction of A␤ with cell membranes was initially proposed by Cotman and co-workers (55), who showed that D-and L-stereoisomers of a truncated form of A␤ induced similar toxicity levels in cultured hippocampal neurons, suggesting that A␤ toxicity does not involve a specific ligand-receptor interaction.…”

Section: Actions Of A␤ On Endogenous Plasmalemmal Ion Channels-mentioning

confidence: 99%

Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

Demuro

Parker

Stutzmann

2010

Journal of Biological Chemistry

359

322

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Lipid Binding to Amyloid β‐Peptide Aggregates: Preferential Binding of Cholesterol as Compared with Phosphatidylcholine and Fatty Acids

Abstract: Amyloid ß-peptide (Aß) aggregates are one of the key neuropathological characteristics of Alzheimer's disease. Aß belongs to a group of proteins that aggregate and form ß-sheets, and some of these proteins bind cholesterol and other lipids.

Cited by 172 publications

References 21 publications

Distribution and Fluidizing Action of Soluble and Aggregated Amyloid β-Peptide in Rat Synaptic Plasma Membranes

Distribution and Fluidizing Action of Soluble and Aggregated Amyloid β-Peptide in Rat Synaptic Plasma Membranes

Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein

Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

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