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

Eckert, Gunter P.; Cairns, Nigel J.; Maras, Athanasios; Gattaz, Wagner F.; Müller, Wernér E.G.

doi:10.1159/000017234

Cited by 134 publications

(82 citation statements)

References 34 publications

(59 reference statements)

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“…[3,5,[33][34][35][36]76,85,89,90,96,111,134]). Of particular interest are those studies that show that not only an increase in the level of cholesterol, but also in the level of the toxic metabolite, 24S-hydroxycholesterol (cerebrosterol) [32,64].…”

Section: Membrane Fluidity In Aging-cholesterolmentioning

confidence: 99%

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane

Yehuda¹,

Rabinovitz²,

Carasso³

et al. 2002

Neurobiology of Aging

353

200

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In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the brain affect the neuronal membrane that is the "site of action" for many essential functions including long-term potentiation (LTP), learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total polyunsaturated fatty acids (PUFA) may result from poor passage rate via the blood-brain barrier, or from a decreased rate of incorporation into the membrane, or a decrease in the activities of delta-6 and delta-9 desaturase enzymes. The added oxidative stress, which leads to an increase of free radicals leading to a decrease in membrane fluidity, may respond to a restricted diet, and thereby overcome the damaging effects of the free radicals. A central focus of this review is that a specific ratio of n-3/n-6 PUFA can restore many of these age-related effects.

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Section: Membrane Fluidity In Aging-cholesterolmentioning

confidence: 99%

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane

Yehuda¹,

Rabinovitz²,

Carasso³

et al. 2002

Neurobiology of Aging

353

200

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“…It has been reported that A␤ is able to form ionic pores (21). A␤ can destroy the structure of brain membranes (22) and may stimulate free radical production by interfering with the regulation of calcium homeostasis and cell enzymatic activity (23). A␤ can also alter the physical-chemical properties of neuronal membranes, including membrane fluidity, membrane lipid dynamics, and the activity of various membrane-bound proteins (24,25).…”

mentioning

confidence: 99%

Cholesterol Is an Important Factor Affecting the Membrane Insertion of β-Amyloid Peptide (Aβ1–40), Which May Potentially Inhibit the Fibril Formation

Sui

2002

Journal of Biological Chemistry

166

155

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␤-Amyloid peptide (A␤), a normal constituent of neuronal and non-neuronal cells, has been proven to be the major component of extracellular plaque of Alzheimer's disease. Interactions between A␤ and neuronal membranes have been postulated to play an important role in the neuropathology of Alzheimer's disease. Here we show that A␤ is able to insert into lipid bilayer. The membrane insertion ability of A␤ is critically controlled by the ratio of cholesterol to phospholipids. In a low concentration of cholesterol A␤ prefers to stay in membrane surface region mainly in a ␤-sheet structure. In contrast, as the ratio of cholesterol to phospholipids rises above 30 mol%, A␤ can insert spontaneously into lipid bilayer by its C terminus. During membrane insertion A␤ generates about 60% ␣-helix and removes almost all ␤-sheet structure. Fibril formation experiments show that such membrane insertion can reduce fibril formation. Our findings reveal a possible pathway by which A␤ prevents itself from aggregation and fibril formation by membrane insertion.The formation of extracellular amyloid plaques is one of the characteristics of Alzheimer's disease. The core component of plaque is A␤, 1 which is the proteolytic product of the larger transmembrane amyloid precursor protein (APP) (1, 2). A␤ contains 39 -42 amino acid residues with a molecular mass of approximate 4 kDa. A␤ is an amphiphilic peptide with a hydrophilic N-terminal domain (residues 1-28) and a hydrophobic C-terminal (residues 29 -40 (42)), the latter corresponding to a part of the transmembrane domain of APP.A␤ is a normal constituent of neuronal and non-neuronal cells (3, 4). It can be detected in cerebrospinal fluid at subnanomolar concentrations in normal individuals. Such a concentration of A␤ has its own physiological functions, for example, increasing tyrosine phosphorylation, increasing the activity of phosphoinositol 3-kinase, and inducing the rapid change of cellular calcium and extracellular protein kinase C (5). It was reported that in cultured hippocampal neurons, A␤ at a low concentration (10 Ϫ11 ϳ10 Ϫ10 M) is neurotrophic to undifferentiated, immature hippocampal neurons (6, 7). As a proteolytic fragment of APP, A␤ can be secreted by membrane-anchored APP or by reinternalized APP (8 -10). Also, A␤ can be degraded either via LRP-mediated endocytosis into primary neurons and astrocytes (11-15) or via scavenger receptor-mediated uptake of aggregates of A␤ into microglial cells (16). The hydrolytic enzymes in lysosomes then can degrade A␤. Thus, whether A␤ is the primary effector of the disease is questioned.Several studies on conformation show that A␤ in the core of amyloid plaques adopts an antiparallel ␤-sheet (17). So A␤ in the form of ␤-sheet may be in favor of aggregating into fibril. In addition, in vitro studies with cell cultures have demonstrated that fibrillar A␤ is toxic to neurons, but monomeric A␤ is not (18 -20). Therefore, the factors inducing A␤ to generate ␤-sheet may contribute to the pathogenesis of Alzheimer's disease.The neurotoxic...

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“…A major focus on the use of diet, cholesterol lowering drugs and lifestyles is to increase neuron number and decrease the size of plaques in the brain with aging. The membrane interactions of Aβ require cholesterol for clearance and metabolism with the increase in the membrane cholesterol involved in the regulation of Aβ assemblies [125][126][127]. The role of caloric restriction in activation of HDAC genes which control membrane cholesterol and the role of phytosterols and phytostanols (Figure 4 [99][100][101][102] have become of central interest since membrane interactions with cholesterol and Aβ may be required for the clearance and metabolism of Aβ.…”

Section: Phytosterols and Cholesterol Homeostasismentioning

confidence: 99%

High Fibre Diets and Alzheimer’s Disease

Martins¹,

Fernando²

2014

FNS

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

Cited by 134 publications

References 34 publications

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane

The role of polyunsaturated fatty acids in restoring the aging neuronal membrane

Cholesterol Is an Important Factor Affecting the Membrane Insertion of β-Amyloid Peptide (Aβ1–40), Which May Potentially Inhibit the Fibril Formation

High Fibre Diets and Alzheimer’s Disease

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