Amyloid β-protein stimulates trafficking of cholesterol and caveolin-1 from the plasma membrane to the Golgi complex in mouse primary astrocytes (original) (raw)
Related papers
Journal of Biological Chemistry, 2003
The Golgi complex plays an important role in cholesterol trafficking in cells, and amyloid -peptides (As) alter cholesterol trafficking. The hypothesis was tested that fresh and aged A-(1-42) would differentially modify Golgi cholesterol content in DINTC1 astrocytes and that the effects of A-(1-42) would be associated with the region of the Golgi complex. Two different methods were used to determine the effects of A-(1-42) on Golgi complex cholesterol. Confocal microscopy showed that fresh A-(1-42) significantly increased cholesterol and that aged A-(1-42) significantly reduced cholesterol content in the Golgi complex. Isolation of the Golgi complex into two fractions using density gradient centrifugation showed effects of aged A-(1-42) similar to those observed with confocal microscopy but revealed the novel finding that fresh A-(1-42) had opposite effects on the two Golgi fractions suggesting a specificity of A-(1-42) perturbation of the Golgi complex. Phosphatidylcholine-phospholipase D activity, cell membrane cholesterol, and apolipoprotein E levels were associated with effects of fresh A-(1-42) on cholesterol distribution but not with effects of aged A-(1-42), arguing against a common mechanism. Extracellular A-(1-42) targets the Golgi complex and disrupts cell cholesterol homeostasis, and this action of A-(1-42) could alter cell functions requiring optimal levels of cholesterol.
Cholesterol and amyloid-beta: Evidence for a cross-talk between astrocytes and neuronal cells
Alzheimer's & Dementia, 2011
Accumulating data support the concept that alterations of cholesterol metabolism might influence the development of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid- (A) peptides in the brain. Changes in the neuronal production of A have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply. In the present study, we tested the hypothesis that A may serve as a signaling molecule capable of informing the astroglial network about the neuronal need for cholesterol. Collectively, our data bolster this hypothesis and demonstrate, for the first time, that A 42 exerts an inhibitory effect on the expression of the cholesterol transporter ABCA1 in cultured astrocytes. Accordingly, we also show that ABCA1 expression is reduced in the brain of APP/PS1 transgenic mice. These results provide a biological function for A peptides and may help to define the pathogenic relationship between cholesterol metabolism in brain and AD.
Cholesterol and amyloid-β: evidence for a cross-talk between astrocytes and neuronal cells
Journal of Alzheimer's disease : JAD, 2011
Accumulating data supports the concept that alterations of cholesterol metabolism might influence the development of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid-β (Aβ) peptides in the brain. Changes in the neuronal production of Aβ have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply. In the present study, we tested the hypothesis that Aβ may serve as a signaling molecule capable of informing the astroglial network about the neuronal need for cholesterol. Collectively, our data bolster this hypothesis and demonstrate, for the first time, that Aβ(42) exerts an inhibitory effect on the expression of the cholesterol transpo...
Journal of Biological Chemistry, 2001
Intercellular cholesterol transport in the brain is carried by high density lipoprotein (HDL) generated in situ by cellular interaction with the apolipoprotein apoE, which is mainly synthesized by astrocytes, and with apoA-I secreted by cells such as endothelial cells. Rat astrocytes in fact generate HDL with extracellular apoA-I in addition to releasing HDL with endogenously synthesized apoE, seemingly by the same mechanism as the HDL assembly for systemic circulation. Relating to this reaction, apoA-I induced translocation of newly synthesized cholesterol and phospholipid to the cytosol prior to extracellular assembly of HDL, accompanied by an increase of caveolin-1 in the cytosol, activation of sterol regulatory element-binding protein, and enhancement of cholesterol synthesis. The lipid translocated into the cytosol was recovered in the fraction with a density of 1.09-1.16 g/ml as well as caveolin-1 and cyclophilin A. Cyclosporin A inhibited these apoA-I-mediated reactions and suppressed apoA-I-mediated cholesterol release. The findings suggest that such translocation of cholesterol and phospholipid into the cytosol is related to the apo A-I-mediated HDL assembly in astrocytes through functional association with caveolin-1 and a cyclosporin A-sensitive cyclophilin protein(s).
Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
2020
ABSTRACTAlzheimer’s Disease (AD) is characterized by the presence of β-Amyloid (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD.In vitroevidence suggests apoE links to Aβ production through nanoscale lipid compartments (also called lipid rafts), but its regulationin vivois unclear. Here we use super-resolution imaging in mouse brain to show apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) into lipid rafts where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid ...
Intracellular Cholesterol Trafficking and Impact in Neurodegeneration
Frontiers in molecular neuroscience, 2017
Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD), however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via s...
Function of b-amyloid in cholesterol transport: a lead to neurotoxicity
Faseb Journal - FASEB J, 2002
Amyloid ß-peptide (Aß), Aß precursor protein (APP), apolipoprotein E (apoE), and elevated cholesterol levels have been linked to Alzheimer's disease (AD) pathology. High cholesterol levels increase APP and apoE expression in human NT2 neuron progenitor cells. A cholesterol- rich environment also induces processing of APP, leading to the formation of Aß and Aß peptide fragments. Using a novel method, we determined that 1) cholesterol binds to Aß at α-secretase cleavage site; 2) Aß17-40 rather than Aß1-40 prevents cholesterol from binding to apoE; 3) Aß1-40 inhibits cholesterol from binding to low-density lipoprotein (LDL), leading to decrease cholesterol influx and intracellular cholesterol levels; 4) the binding of cholesterol to apoE or LDL was abolished completely in presence of Aß1-42. Increased extracellular free cholesterol levels are toxic to neurons; this toxicity is prevented by specific lipoproteins, such as high- density lipoproteins, which maintain their ability to b...
Molecular Biology of the Cell, 2005
Caveolins are a crucial component of plasma membrane (PM) caveolae but have also been localized to intracellular compartments including the Golgi complex and lipid bodies. Mutant caveolins associated with human disease show aberrant trafficking to the PM and Golgi accumulation. We now show that the Golgi pool of mainly newlysynthesized protein is detergent-soluble and predominantly in a monomeric state, in contrast to the surface pool. Caveolin at the PM is not recognised by specific caveolin antibodies unless PM cholesterol is depleted. Exit from the Golgi complex of wild type caveolin-1 or -3 , but not VSV-G protein, is modulated by changing cellular cholesterol levels. In contrast, a muscular dystrophy-associated mutant of caveolin-3, Cav3P104L, showed increased accumulation in the Golgi complex upon cholesterol treatment. In addition, we demonstrate that in response to fatty acid treatment caveolin can follow a previously undescribed pathway from the PM to lipid bodies and can move from lipid bodies to the PM in response to removal of fatty acids. The results suggest that cholesterol is a rate limiting component for caveolin trafficking. Changes in caveolin flux through the exocytic pathway can therefore be an indicator of cellular cholesterol and fatty acid levels.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Generation of amyloid-beta (Abeta) from the amyloid precursor protein (APP) requires proteolytic cleavage by two proteases, beta- and gamma-secretase. Several lines of evidence suggest a role for cholesterol on secretase activities, although the responsible cellular mechanisms remain unclear. Here we show that alterations in cholesterol transport from late endocytic organelles to the endoplasmic reticulum have important consequences for both APP processing and the localization of gamma-secretase-associated presenilins (PS). Exposure of neuronal cells to cholesterol transport-inhibiting agents resulted in a marked decrease in beta-cleavage of full-length APP. In contrast, gamma-secretase activity on APP C-terminal fragments was enhanced, increasing the production of both Abeta40 and Abeta42. Remarkably, retention of cholesterol in endosomal/lysosomal compartments induced PS1 and PS2 to accumulate in Rab7-positive vesicular organelles implicated in cholesterol sorting. Accumulation of...
International Journal of Molecular Sciences
The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to...