Multiple inhibitory effects of Alzheimer's peptide Aβ1–40 on lipid biosynthesis in cultured human HepG2 cells

Koudinova, Natalia V.; Березов, Т. Т.; Koudinov, Alexei R.

doi:10.1016/0014-5793(96)01042-3

Cited by 26 publications

(18 citation statements)

References 19 publications

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“…One of the possible explanations is that processing of ␤APP is modulated by a change in the cellular content of cholesterol (Bodovitz and Klein, 1996;Racchi et al, 1997). Alternatively, it is also possible that cholesterol metabolism is perturbed via its interaction with A␤ (Koudinova et al, 1996;Avdulov et al, 1997) and that apoE4 accelerates this A␤-induced perturbation of cholesterol metabolism, leading to the neuronal cell death via impairment in the structural and functional integrity of membrane proteins.…”

Section: Discussionmentioning

confidence: 95%

Apolipoprotein E4 induces neuronal cell death under conditions of suppressed de novo cholesterol synthesis

Michikawa

Yanagisawa

1998

J. Neurosci. Res.

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The presence of the apolipoprotein E (apoE) allele epsilon4 is a major risk factor for the development of Alzheimer's disease (AD); however, the molecular mechanism underlying the acceleration of AD development in individuals with epsilon4 remains to be determined. To investigate the isoform-specific effects of apoE on neurons, primary neuron cultures were prepared from fetal rat cerebral cortices. Inhibition by compactin, a 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor of de novo cholesterol synthesis, induced premature neuronal cell death in a dose-dependent manner. In the presence of compactin at a sublethal dose to the cells, rabbit beta-migrating very low density lipoprotein (beta-VLDL) with human apoE4 (the product of epsilon4) induced premature neuronal cell death, while that with apoE3 (the product of epsilon3) did not. Neurons cultured in the presence of apoE4, beta-VLDL, and compactin were shrunken and spherical, containing condensed chromatin and fragmented DNA, features characteristic of apoptosis. The addition of intermediate metabolites of the cholesterol biosynthetic pathway, including mevalonate and squalene, rescued neuronal cells incubated with apoE4 and beta-VLDL, in the presence of compactin. These results strongly suggest that a reduction in the level of endogenously synthesized cholesterol is a prerequisite for apoE4-induced neuronal cell death.

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Section: Discussionmentioning

confidence: 95%

Apolipoprotein E4 induces neuronal cell death under conditions of suppressed de novo cholesterol synthesis

Michikawa

Yanagisawa

1998

J. Neurosci. Res.

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“…On the other hand, as reported previously, Ah itself affects the key steps of cholesterol homeostasis including cellular uptake, efflux, esterification and synthesis. The latter effect is different in liver, and thus is tissue specific [12,13]. While the above complex relation is of major importance for normal synaptic function, plasticity (activity-dependent, developmental and under recovery from injury), neurodegeneration, and sporadic AD, the functional interaction of APP, Ah and cholesterol also explains genetic predisposition to neurodegeneration in rare familial AD cases having APP or presenilin (PS) mutations, and in Down syndrome, a trisomy 21 (see below).…”

Section: Amyloid Precursor Protein (App) and Ab Protein Are Integratementioning

confidence: 93%

Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

Koudinov

Koudinova

2005

Journal of the Neurological Sciences

111

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“…Aβ peptides modulate the metabolism of cholesterol, in particular its esterification rate, and of phospholipids in hepatocytes, neuronal cells, and in the entire brain (Koudinov et al, 1996; Koudinova et al, 1996, 2000). It was also found that Aβ peptides alter vesicle trafficking and cholesterol homeostasis (Liu et al, 1998).…”

Section: Lipid Raft Components and Their Changes In Admentioning

confidence: 99%

Lipid Rafts and Alzheimer’s Disease: Protein-Lipid Interactions and Perturbation of Signaling

Hicks¹,

Nalivaeva²,

Turner³

2012

Front. Physio.

171

176

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Lipid rafts are membrane domains, more ordered than the bulk membrane and enriched in cholesterol and sphingolipids. They represent a platform for protein-lipid and protein–protein interactions and for cellular signaling events. In addition to their normal functions, including membrane trafficking, ligand binding (including viruses), axonal development and maintenance of synaptic integrity, rafts have also been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD). Lipid rafts promote interaction of the amyloid precursor protein (APP) with the secretase (BACE-1) responsible for generation of the amyloid β peptide, Aβ. Rafts also regulate cholinergic signaling as well as acetylcholinesterase and Aβ interaction. In addition, such major lipid raft components as cholesterol and GM1 ganglioside have been directly implicated in pathogenesis of the disease. Perturbation of lipid raft integrity can also affect various signaling pathways leading to cellular death and AD. In this review, we discuss modulation of APP cleavage by lipid rafts and their components, while also looking at more recent findings on the role of lipid rafts in signaling events.

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Multiple inhibitory effects of Alzheimer's peptide Aβ1–40 on lipid biosynthesis in cultured human HepG2 cells

Cited by 26 publications

References 19 publications

Apolipoprotein E4 induces neuronal cell death under conditions of suppressed de novo cholesterol synthesis

Apolipoprotein E4 induces neuronal cell death under conditions of suppressed de novo cholesterol synthesis

Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

Lipid Rafts and Alzheimer’s Disease: Protein-Lipid Interactions and Perturbation of Signaling

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