X‐Ray Diffraction Analysis of Brain Lipid Membrane Structure in Alzheimer's Disease and β‐Amyloid Peptide Interactionsa

Mason, R. Preston; Shajenko, Lydia

doi:10.1111/j.1749-6632.1993.tb23027.x

Cited by 17 publications

(9 citation statements)

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“…It is well documented that Aß alters the structure and integrity of artificial and biological membranes, including human cortical tissue [10,15,38,39]. The present findings confirm this effect for human hippocampal membranes.…”

Section: Discussionsupporting

confidence: 81%

Cholesterol Modulates the Membrane- Disordering Effects of Beta-Amyloid Peptides in the Hippocampus: Specific Changes in Alzheimer’s Disease

Eckert¹,

Cairns²,

Maras³

et al. 2000

Dement Geriatr Cogn Disord

134

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Cholesterol represents an important determinant of the physical state of biological membranes. In Alzheimer’s disease (AD) brains, specific changes in the distribution of cholesterol and its membrane-ordering effects take place. In the present study, membrane fluidity was investigated at the level of the hydrocarbon core and of the heads of the phospholipid bilayers using two different fluorescent probes. Hippocampal membranes of AD brains showed a reduced fluidity in the hydrocarbon core region only. Fluidity was correlated with the cholesterol content in AD and control membranes. Aggregated β-amyloid peptides (Aβ) disrupted brain membrane structure in AD patients and controls in the same fashion. However, this effect was correlated with the cholesterol content in AD membranes only. It is suggested that in AD the brain becomes specifically sensitive for the modulation by membrane-bound cholesterol of the membrane-disturbing and ultimately neurotoxic properties of Aβ.

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Section: Discussionsupporting

confidence: 81%

Cholesterol Modulates the Membrane- Disordering Effects of Beta-Amyloid Peptides in the Hippocampus: Specific Changes in Alzheimer’s Disease

Eckert¹,

Cairns²,

Maras³

et al. 2000

Dement Geriatr Cogn Disord

134

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“…The importance of membrane composition in A␤ formation, A␤ membrane association, and A␤ aggregation has been established previously (63)(64)(65). Charged phospholipids, cholesterol, and gangliosides have all been cited frequently (19,(21)(22)(23)(24) as playing an important role in A␤-membrane interactions.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Rymer

Good

2001

Journal of Biological Chemistry

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␤-Amyloid (A␤) is the primary protein component of senile plaques associated with Alzheimer's disease and has been implicated in the neurotoxicity associated with the disease. A variety of evidence points to the importance of A␤-membrane interactions in the mechanism of A␤ neurotoxicity and indicates that cholesterol and gangliosides are particularly important for A␤ aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on A␤-induced GTPase activity in cells, a step implicated in the mechanism of A␤ toxicity, and A␤-induced cell toxicity. Cholesterol reduction and depletion of membraneassociated sialic acid residues both significantly reduced the A␤-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from A␤-induced toxicity. These results indicate the importance of A␤-membrane interactions in the mechanism of A␤ toxicity. In addition, these results suggest that control of cellular cholesterol and/or ganglioside content may prove useful in the prevention or treatment of Alzheimer's disease.An important pathological hallmark of Alzheimer's disease (AD) 1 is the formation and progressive deposition of insoluble amyloid fibrils within the cerebral cortex (1). The key constituent of these amyloid deposits has been identified as a 39 -43-amino acid long polypeptide, ␤-amyloid peptide (A␤), which is derived primarily from the proteolytic cleavage of a much larger amyloid precursor protein (2). Presenilin 1 and 2 are believed to be involved in the proteolytic processing of the A␤ fragment (3-6). Evidence for the causative role of A␤ in the pathogenesis of AD partly comes from genetic studies, which linked mutations in the amyloid precursor protein and in the presenilins to inheritable forms of AD (7-9). Further evidence originates from in vitro toxicity studies with synthetic A␤ peptides, which have shown that A␤, in an aggregated state (fibril, protofibril, low molecular weight oligomer, or diffusible, nonfibrillar ligand), is toxic to neurons in culture (10 -17). Although it seems certain that A␤ plays a role in neurotoxicity associated with AD, the molecular mechanism of A␤ neurotoxicity remains unclear.Increasing evidence indicates that the neuronal cell membrane is important in the mechanism of A␤ toxicity. Studies (18 -21) have indicated that membrane components such as cholesterol and gangliosides alter the affinity of A␤ for phospholipid membranes. Once associated with the membranes, negatively charged phospholipids, cholesterol, and gangliosides have been shown to increase the ␤-sheet content and/or rate of aggregation of A␤ (19,(21)(22)(23)(24). Both in vivo and in vitro, alterations in soluble cholesterol and/or cholesterol biosynthesis have also been shown to affect the normal processing of amyloid precursor protein (25)(26)(27). In these studies, the inhibition of cholesterol synthesis led to decreased A␤ formation (25,27). In...

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“…Recent papers suggest that cholesterol levels regulate Aβ production and Alzheimer's disease pathology by acting on the multiple enzymes which regulate the APP processing [16–18]. X‐ray diffraction studies show that membranes isolated from AD brains are thinner than those obtained from age‐matched control brains [19]. This alteration in membrane thickness may change the spatial relationship between membrane‐associated proteases and APP, modifying the amyloidogenic cleavage of the protein.…”

mentioning

confidence: 99%

The amyloid precursor protein interacts with neutral lipids

Lahdo

Coillet-Matillon

Chauvet³

et al. 2002

European Journal of Biochemistry

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The amyloid protein precursor (APP) was incorporated into liposomes or phospholipid monolayers. APP insertion into liposomes required neutral lipids, such as L-a-phosphatidylcholine, in the target membrane. It was prevented in vesicles containing L-a-phosphatidylserine. The insertion was enhanced in acidic solutions, suggesting that it is modulated by specific charge/charge interactions. Surfaceactive properties and behaviour of APP were characterized during insertion of the protein in monomolecular films of L-a-phosphatidylcholine, L-a-phosphatidylethanolamine or L-a-phosphatidylserine. The presence of the lipid film enhanced the rate of adsorption of the protein at the interface, and the increase in surface pressure was consistent with APP penetrating the lipid film. The adsorption of APP on the lipid monolayers displayed a significant head group dependency, suggesting that the changes in surface pressure produced by the protein were probably affected by electrostatic interactions with the lipid layers. Our results indicate that the penetration of the protein into the lipid monolayer is also influenced by the hydrophobic interactions between APP and the lipid. CD spectra showed that a large proportion of the a-helical secondary structure of APP remained preserved over the pH or ionic strength ranges used. Our findings suggest that APP/membrane interactions are mediated by the lipid composition and depend on both electrostatic and hydrophobic effects, and that the variations observed are not due to major secondary structural changes in APP. These observations may be related to the partitioning of APP into membrane microdomains.

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X‐Ray Diffraction Analysis of Brain Lipid Membrane Structure in Alzheimer's Disease and β‐Amyloid Peptide Interactionsa

Cited by 17 publications

References 0 publications

Cholesterol Modulates the Membrane- Disordering Effects of Beta-Amyloid Peptides in the Hippocampus: Specific Changes in Alzheimer’s Disease

Cholesterol Modulates the Membrane- Disordering Effects of Beta-Amyloid Peptides in the Hippocampus: Specific Changes in Alzheimer’s Disease

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

The amyloid precursor protein interacts with neutral lipids

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