scholarly journals Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction

Acta Naturae ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 58-73 ◽  
Author(s):  
A. M. Petrov ◽  
M. R. Kasimov ◽  
A. L. Zefirov
Keyword(s):  
Plasma Membrane ◽  
Synaptic Transmission ◽  
Neurodegenerative Diseases ◽  
Plasma Membranes ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
Brain Cholesterol ◽  
Cholesterol Biosynthetic Pathway ◽  
Niemann Pick

Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the bodys total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntingtons, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimers disease, Parkinsons disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

scholarly journals Defective insulin receptor activation and altered lipid rafts in Niemann–Pick type C disease hepatocytes

2005 ◽  
Vol 391 (3) ◽  
pp. 465-472 ◽  
Author(s):  
Saara Vainio ◽  
Igor Bykov ◽  
Martin Hermansson ◽  
Eija Jokitalo ◽  
Pentti Somerharju ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Receptor ◽  
Lipid Rafts ◽  
Plasma Membranes ◽  
Cholesterol Content ◽  
Receptor Activation ◽  
Membrane Lipid ◽  
Plasma Membrane Receptor ◽  
Type C ◽  
Niemann Pick

Niemann–Pick type C (NPC) disease is a neuro-visceral cholesterol storage disorder caused by mutations in the NPC-1 or NPC-2 gene. In the present paper, we studied IR (insulin receptor) activation and the plasma-membrane lipid assembly in primary hepatocytes from control and NPC1–/– mice. We have previously reported that, in hepatocytes, IR activation is dependent on cholesterol–sphingolipid rafts [Vainio, Heino, Mansson, Fredman, Kuismanen, Vaarala and Ikonen (2002) EMBO Rep. 3, 95–100]. We found that, in NPC hepatocytes, IR levels were up-regulated and the receptor activation was compromised. Defective IR activation was reproduced in isolated NPC plasma-membrane preparations, which displayed an increased cholesterol content and saturation of major phospholipids. The NPC plasma membranes were less fluid than control membranes as indicated by increased DPH (1,6-diphenyl-1,3,5-hexatriene) fluorescence anisotropy values. Both in NPC hepatocytes and plasma-membrane fractions, the association of IR with low-density DRMs (detergent-resistant membranes) was increased. Moreover, the detergent resistance of both cholesterol and phosphatidylcholine were increased in NPC membranes. Finally, cholesterol removal inhibited IR activation in control membranes but restored IR activation in NPC membranes. Taken together, the results reveal a lipid imbalance in the NPC hepatocyte, which increases lipid ordering in the plasma membrane, alters the properties of lipid rafts and interferes with the function of a raft-associated plasma-membrane receptor. Such a mechanism may participate in the pathogenesis of NPC disease and contribute to insulin resistance in other disorders of lipid metabolism.

scholarly journals Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Vijay R. Varma ◽  
H. Büşra Lüleci ◽  
Anup M. Oommen ◽  
Sudhir Varma ◽  
Chad T. Blackshear ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Transcriptomic Data ◽  
Brain Cholesterol ◽  
Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

scholarly journals Targeting cytochrome P450 46A1 and brain cholesterol 24-hydroxylation to treat neurodegenerative diseases

2021 ◽  
Author(s):  
Irina Pikuleva
Keyword(s):  
Cytochrome P450 ◽  
Motor Behavior ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
Brain Diseases ◽  
Protein Accumulation ◽  
Brain Cholesterol ◽  
Tightly Coupled ◽  
The Brain

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in the case of neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory, and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

scholarly journals The Fruit Fly Drosophila melanogaster as a Model System to Study Cholesterol Metabolism and Homeostasis

Cholesterol ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Ryusuke Niwa ◽  
Yuko S. Niwa
Keyword(s):  
Drosophila Melanogaster ◽  
Steroid Hormones ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Fruit Fly ◽  
Model System ◽  
Biophysical Properties ◽  
Type C ◽  
Niemann Pick

Cholesterol has long been recognized for its versatile roles in influencing the biophysical properties of cell membranes and for serving as a precursor of steroid hormones. While many aspects of cholesterol biosynthesis are well understood, little is currently known about the molecular mechanisms of cholesterol metabolism and homeostasis. Recently, genetic approaches in the fruit fly, Drosophila melanogaster, have been successfully used for the analysis of molecular mechanisms that regulate cholesterol metabolism and homeostasis. This paper summarizes the recent studies on genes that regulate cholesterol metabolism and homeostasis, including neverland, Niemann Pick type C(NPC) disease genes, and DHR96.

scholarly journals Lipids analysis in hemolymph of African giant Achatina fulica (Bowdich, 1822) exposed to different photoperiods

2010 ◽  
Vol 70 (1) ◽  
pp. 129-134 ◽  
Author(s):  
D. Lustrino ◽  
VM. Tunholi-Alves ◽  
VM. Tunholi ◽  
MP. Marassi ◽  
J. Pinheiro
Keyword(s):  
Total Cholesterol ◽  
Cell Membranes ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
Achatina Fulica ◽  
Negative Relation ◽  
Post Exposure ◽  
Lipids Analysis ◽  
Lipids Metabolism

The influence of different photophases (0, 6, 12, 18 and 24 hours) on the triglycerides and total cholesterol contents in the hemolymph of A. fulica was evaluated, since there is no information in the literature about the influence of this factor on lipids metabolism in mollusks. After 2 and 4 weeks of exposure the snails were dissected. The cholesterol content at the 2nd and 4th weeks post exposure only varied significantly in the groups exposed at 24 hours and 0 hour of photophase, respectively. Probably, such increase may be a result of a rise in cholesterol biosynthesis and/or remodelling of cell membranes. There were no significant differences among the content of triglycerides in the snails exposed to 6, 12, 18 and 24 hours of photophase during two weeks. The snails exposed to intermediate photophase (6 and 12 hours) had the triglycerides content increased, ranging over values near to those observed in the group exposed to 0 hour. Results showed that triglycerides metabolism in A. fulica are more influenced by photoperiod than cholesterol metabolism. A negative relation is maintained between the triglycerides content in the hemolymph and the different photophases, with lower mobilisation of triglycerides under shorter photophases.

Topology of morphologically detectable protein and cholesterol in membranes of polypeptide-secreting cells

1981 ◽  
Vol 296 (1080) ◽  
pp. 47-54 ◽  
Keyword(s):  
Plasma Membrane ◽  
Secretory Granule ◽  
Plasma Membranes ◽  
Secretory Pathway ◽  
Freeze Fracture ◽  
Fracture Morphology ◽  
Cholesterol Content ◽  
Intramembrane Particles ◽  
Exocrine Cells ◽  
Luminal Membrane

The freeze-fracture morphology of intracellular and plasma membranes in endocrine and exocrine polypeptide-secreting cells has been studied to detect changes while these membranes interact during secretion. A qualitative and quantitative evaluation of intramembrane particles and filipin binding as indicators of protein and cholesterol content of the membranes, respectively, reveals the following changes. From the forming of the maturing pole of the Golgi complex, membranes lose morphologically detectable protein and gain morphologically detectable cholesterol. The protein-poor, cholesterol-rich secretory granule membrane then interacts with a richly particulate plasma membrane in endocrine cells and with a moderately particulate luminal membrane in exocrine cells. The site of interaction between secretory granule and plasma membrane is characterized by a local clearing of intramembrane particles; by contrast, filipin-binding sites revealing cholesterol are present in this area. In exocrine cells, the fused secretory granule, which is initially rich in filipin-cholesterol complexes and poor in particles, appears to lose progressively its filipin labelling to resemble the poorly labelled luminal membrane. These findings, although they cannot be interpreted definitely at present, clearly show impressive changes of membrane structure along the secretory pathway and suggest that a corresponding degree of functional specialization is needed for proper interaction to occur.

scholarly journals Distinct pathways of cholesterol biosynthesis impact on insulin secretion

2014 ◽  
Vol 224 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Juan P Zúñiga-Hertz ◽  
Eduardo Rebelato ◽  
Adam Kassan ◽  
Abdelrahman M Khalifa ◽  
Sameh S Ali ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Membrane Fluidity ◽  
Structural Integrity ◽  
Cell Function ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
Paramagnetic Resonance ◽  
Cellular Cholesterol ◽  
Plasma Membrane Fluidity

Results from previous investigations have indicated that glucose-stimulated insulin secretion (GSIS) is affected by changes in cholesterol and its intermediates, but the precise link between secretion and cholesterol has not been thoroughly investigated. In this study, we show the contribution of both protein isoprenylation and cholesterol-dependent plasma membrane structural integrity to insulin secretion in INS-1E cells and mouse islets. Acute (2 h) inhibition of hydroxyl-methylglutaryl-CoA reductase by simvastatin (SIM) resulted in inhibition of GSIS without reduction in total cellular cholesterol content. This effect was prevented by cell loading with the isoprenyl molecule geranylgeranyl pyrophosphate. Chronic (24 h) inhibition of cholesterol biosynthesis resulted in inhibition of GSIS with a significant reduction in total cellular cholesterol content, which was also observed after the inhibition of cholesterol biosynthesis downstream of isoprenoid formation. Electron paramagnetic resonance analyses of INS-1E cells showed that the SIM-induced reduction in cholesterol increased plasma membrane fluidity. Thus, the blockade of cholesterol biosynthesis resulted in the reduction of availability of isoprenoids, followed by a reduction in the total cholesterol content associated with an increase in plasma membrane fluidity. Herein, we show the different contributions of cholesterol biosynthesis to GSIS, and propose that isoprenoid molecules and cholesterol-dependent signaling are dual regulators of proper β-cell function.

Modulation of receptor-mediated gonadotropin action in rat testes by dietary fat

1988 ◽  
Vol 254 (6) ◽  
pp. E708-E712
Author(s):  
E. Sebokova ◽  
M. L. Garg ◽  
M. T. Clandinin
Keyword(s):  
Plasma Membrane ◽  
Adenylate Cyclase ◽  
Linolenic Acid ◽  
Plasma Membranes ◽  
Saturated Fatty Acids ◽  
Phospholipid Composition ◽  
Cholesterol Content ◽  
Cyclase Activity ◽  
Adenylate Cyclase Activity ◽  
Hcg Receptor

The effect of feeding diets enriched with 18:2 omega 6, 18:3 omega 3, or saturated fatty acids on lipid composition and receptor-mediated action of luteinizing hormone/human chorionic gonadotropin (LH/hCG) in rat testicular plasma membranes was investigated. Linoleic and alpha-linolenic acid treatments reduced total phospholipid and cholesterol content of the testicular plasma membrane and altered membrane phospholipid composition. Change in phospholipid and cholesterol content after feeding the polyunsaturated fats decreased cholesterol to phospholipid ratios and binding capacity of the LH/hCG receptor in the testicular plasma membrane. LH-stimulated adenylate cyclase activity was decreased in animals fed the linolenic acid-rich diet. NaF-stimulated adenylate cyclase activity was decreased in animals fed diets high in either polyunsaturated fatty acid. Decreased plasma membrane LH/hCG receptor content was associated with decreased testosterone production in Leydig cells in response to LH in the linolenic acid-fed group. It is suggested that change in cholesterol-to-phospholipid ratios alters the physical properties of testicular plasma membranes in a manner that influences accessibility of LH/hCG receptors in testicular tissue.

scholarly journals Freeze-fracture studies of photoreceptor membranes: new observations bearing upon the distribution of cholesterol.

1983 ◽  
Vol 97 (3) ◽  
pp. 749-755 ◽  
Author(s):  
L D Andrews ◽  
A I Cohen
Keyword(s):  
New York ◽  
Plasma Membrane ◽  
Outer Segment ◽  
Plasma Membranes ◽  
Prolonged Exposure ◽  
Freeze Fracture ◽  
Cholesterol Content ◽  
Apical Plasma Membrane ◽  
Frog Neuromuscular Junction ◽  
Vertebrate Photoreceptor

We performed electron microscopy of replicas from freeze-fractured retinas exposed during or after fixation to the cholesterol-binding antibiotic, filipin. We observed characteristic filipin-induced perturbations throughout the disk and plasma membranes of retinal rod outer segments of various species. It is evident that a prolonged exposure to filipin in fixative enhances rather than reduces presumptive cholesterol detection in the vertebrate photoreceptor cell. In agreement with the pattern seen in our previous study (Andrews, L.D., and A. I. Cohen, 1979, J. Cell Biol., 81:215-228), filipin-binding in membranes exhibiting particle-free patches seemed largely confined to these patches. Favorably fractured photoreceptors exhibited marked filipin-binding in apical inner segment plasma membrane topologically confluent with and proximate to the outer segment plasma membrane, which was comparatively free of filipin binding. A possible boundary between these differing membrane domains was suggested in a number of replicas exhibiting lower filipin binding to the apical plasma membrane of the inner segment in the area surrounding the cilium. This area contains a structure (Andrews, L. D., 1982, Freeze-fracture studies of vertebrate photoreceptors, In Structure of the Eye, J. G. Hollyfield and E. Acosta Vidrio, editors, Elsevier/North-Holland, New York, 11-23) that resembles the active zones of the nerve terminals for the frog neuromuscular junction. These observations lead us to hypothesize that these structures may function to direct vesicle fusion to occur near them, in a domain of membrane more closely resembling outer than inner segment plasma membrane. The above evidence supports the views that (a) all disk membranes contain cholesterol, but the particle-free patches present in some disks trap cholesterol from contiguous particulate membrane regions; (b) contiguous inner and outer segment membranes may greatly differ in cholesterol content; and (c) the suggested higher cholesterol in the inner segment than in the outer segment plasma membrane may help direct newly inserted photopigment molecules to the outer segment.

scholarly journals Cholesterol in the Pathogenesis of Alzheimer’s, Parkinson’s Diseases and Autism: Link to Synaptic Dysfunction

Acta Naturae ◽  
2017 ◽  
Vol 9 (1) ◽  
pp. 26-37 ◽  
Author(s):  
A. M. Petrov ◽  
M. R. Kasimov ◽  
A. L. Zefirov
Keyword(s):  
Autism Spectrum Disorders ◽  
Neurodegenerative Diseases ◽  
Cholesterol Metabolism ◽  
Autism Spectrum ◽  
Cholesterol Homeostasis ◽  
Membrane Cholesterol ◽  
Brain Cholesterol ◽  
Parkinson’S Diseases ◽  
Spectrum Disorders ◽  
Key Steps

In our previous review, we described brain cholesterol metabolism in control conditions and in the case of some rare neurological pathologies linked to defects in the genes which are directly involved in the synthesis and/or traffic of cholesterol. Here, we have analyzed disruptions in cholesterol homeostasis in widespread neurodegenerative diseases (Alzheimers and Parkinsons diseases) and autism spectrum disorders. We particularly focused on the synaptic dysfunctions that could arise from changes in both membrane cholesterol availability and oxysterol production. Notably, alterations in the brain cholesterol metabolism and neurotransmission occur in the early stages of these pathologies and the polymorphism of the genes associated with cholesterol homeostasis and synaptic communication affects the risk of onset and severity of these diseases. In addition, pharmacological and genetic manipulations of brain cholesterol homeostasis in animal models frequently have marked effects on the progression of neurodegenerative diseases. Thus, the development of Alzheimers, Parkinsons and autism spectrum disorders may be partially associated with an imbalance of cholesterol homeostasis that leads to changes in the membrane cholesterol and oxysterol levels that, in turn, modulates key steps in the synaptic transmission.

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