Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

Koudinov, Alexei R.; Koudinova, Natalia V.

doi:10.1016/j.jns.2004.11.036

Cited by 110 publications

(91 citation statements)

References 32 publications

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“…cDNA was synthesized from 1.5 g of total RNA using oligo(dT) [12][13][14][15][16][17][18] random primers and Superscript II reverse transcriptase (Invitrogen) according to the manufacturer's instructions. Real-time qPCR was performed using Platinum Quantitation PCR supermix (Invitrogen), SYBR Green I (Molecular Probes), and intron-spanning, gene-specific oligonucleotides (250 nM of each primer) in a total volume of 25 l. Transcripts were detected by real-time qPCR with a Rotor-Gene 3000 instrument (Montreal Biotech, Montreal, Quebec, Canada).…”

Section: Methodsmentioning

confidence: 99%

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Expression of ABCG1, but Not ABCA1, Correlates with Cholesterol Release by Cerebellar Astroglia

Karten

Campenot

Vance

et al. 2006

Journal of Biological Chemistry

114

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Central nervous system lipoproteins mediate the exchange of cholesterol between cells and support synaptogenesis and neuronal growth. The primary source of lipoproteins in the brain is astroglia cells that synthesize and secrete apolipoprotein (apo) E in high density lipoprotein-like particles. Small quantities of apoA1, derived from the peripheral circulation, are also present in the brain. In addition to the direct secretion of apoE-containing lipoproteins from astroglia, glia-derived lipoproteins are thought to be formed by cholesterol efflux to extracellular apolipoproteins via ATP-binding cassette (ABC) transporters. We used cultured cerebellar murine astroglia to investigate the relationship among cholesterol availability, apoE secretion, expression of ABCA1 and ABCG1, and cholesterol efflux. In many cell types, cholesterol content, ABCA1 expression, and cholesterol efflux are closely correlated. In contrast, cholesterol enrichment of glia failed to increase ABCA1 expression, although ABCG1 expression and cholesterol efflux to apoA1 were increased. Moreover, the liver X receptor (LXR) agonist TO901317 up-regulated ABCA1 and ABCG1 expression in glia without stimulating cholesterol efflux. Larger lipoproteins were generated when glia were enriched with cholesterol, whereas treatment with the LXR agonist produced smaller particles that were eliminated when the glia were loaded with cholesterol. We also used glia from ApoE ؊/؊ mice to distinguish between direct lipoprotein secretion and the extracellular generation of lipoproteins. Our observations indicate that partially lipidated apoE, secreted directly by glia, is likely to be the major extracellular acceptor of cholesterol released from glia in a process mediated by ABCG1.The human brain contains 15-20% of total body cholesterol but represents only ϳ5% of total body weight (1). Cholesterol is a key component of all membranes, including myelin, in the central nervous system (CNS), 4 and cholesterol is synthesized continuously, albeit at a low rate, in the adult brain (1). All cholesterol in the CNS is synthesized within the CNS rather than being imported from the periphery (2). As a mechanism for maintaining cholesterol homeostasis in the CNS, cholesterol can be converted into the more polar 24-hydroxycholesterol, which is released into the circulation by a subset of neurons (3, 4). Because cholesterol metabolism and distribution are not uniform across all cell types of the brain, an efficient system is necessary for the transport of cholesterol, and probably other lipids, among cells of the CNS. In the CNS, as in the periphery, cholesterol exchange between cells is mediated by lipoproteins. Lipoproteins in the CNS are derived from glia (astrocytes and microglia), which synthesize and secrete apolipoprotein (apo) E and apoJ (5-7) as well as apoD (8). Unlike the plasma, in which apoA1 is the most abundant apolipoprotein, apoE is the major apolipoprotein in the CNS (9, 10). Glia-derived lipoproteins play important roles in the brain by enhancing synaptogenesi...

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Section: Methodsmentioning

confidence: 99%

“…16). Moreover, imbalances in cholesterol homeostasis in the CNS have been proposed to cause synaptic dysfunction (17).…”

mentioning

confidence: 99%

Expression of ABCG1, but Not ABCA1, Correlates with Cholesterol Release by Cerebellar Astroglia

Karten

Campenot

Vance

et al. 2006

Journal of Biological Chemistry

114

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“…As physicochemical properties of membranes are altered during aging and neurodegeneration, it is clear that any imbalance of proportion of lipids in membranes and/or changed ratio of membrane lipids may contribute and further complicate AD pathology [18]. Indeed, there have been a lot of studies so far which provided the data on possible roles of cholesterol and APP processing in lipid domaines in AD pathology [10]. Also, several other studies revealed that GM1 ganglioside may act as an endogenous seed for amyloidogenesis, interacting with amyloid protein [4] and [23].…”

Section: Commentmentioning

confidence: 99%

Ganglioside catabolism is altered in fibroblasts and leukocytes from Alzheimer's disease patients

Kalanj-Bognar

2006

Neurobiology of Aging

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“…It has been shown that animals fed a diet supplemented with 2% cholesterol have increased A in the brain cortex and hippocampus. Furthermore, impaired brain cholesterol dynamics have been described as a potential cause of AD [19].…”

Section: Introductionmentioning

confidence: 99%

The Mthfr 677t Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer'Sdisease in an Egyptian Population

Hewedi

Elhawary

2015

European Psychiatry

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Objective. We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimer's disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Methods. Forty-three Alzheimer's cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. Results. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls ( = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. Conclusions. The MTHFR 677C>T polymorphism-especially the presence of one copy of the T allele-appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.

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Cholesterol homeostasis failure as a unifying cause of synaptic degeneration

Cited by 110 publications

References 32 publications

Expression of ABCG1, but Not ABCA1, Correlates with Cholesterol Release by Cerebellar Astroglia

Expression of ABCG1, but Not ABCA1, Correlates with Cholesterol Release by Cerebellar Astroglia

Ganglioside catabolism is altered in fibroblasts and leukocytes from Alzheimer's disease patients

The Mthfr 677t Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer'Sdisease in an Egyptian Population

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