Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis.
Dodge James C,Jensen Elizabeth H,Yu Jinlong,Sardi S Pablo,Bialas Allison R,Taksir Tatyana V,Bangari Dinesh S,Shihabuddin Lamya S
The Journal of neuroscience : the official journal of the Society for Neuroscience
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1 mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1 mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS. Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.
10.1523/JNEUROSCI.1388-20.2020
Biomarkers of Amyotrophic Lateral Sclerosis: Current Status and Interest of Oxysterols and Phytosterols.
Vejux Anne,Namsi Amira,Nury Thomas,Moreau Thibault,Lizard Gérard
Frontiers in molecular neuroscience
Amyotrophic lateral sclerosis (ALS) is a non-demyelinating neurodegenerative disease in adults with motor disorders. Two forms exist: a sporadic form (90% of cases) and a family form due to mutations in more than 20 genes including the Superoxide dismutase 1, TAR DNA Binding Protein, Fused in Sarcoma, chromosome 9 open reading frame 72 and VAPB genes. The mechanisms associated with this pathology are beginning to be known: oxidative stress, glutamate excitotoxicity, protein aggregation, reticulum endoplasmic stress, neuroinflammation, alteration of RNA metabolism. In various neurodegenerative diseases, such as Alzheimer's disease or multiple sclerosis, the involvement of lipids is increasingly suggested based on lipid metabolism modifications. With regard to ALS, research has also focused on the possible involvement of lipids. Lipid involvement was suggested for clinical arguments where changes in cholesterol and LDL/HDL levels were reported with, however, differences in positivity between studies. Since lipids are involved in the membrane structure and certain signaling pathways, it may be considered to look for oxysterols, mainly 25-hydroxycholesterol and its metabolites involved in immune response, or phytosterols to find suitable biomarkers for this pathology.
10.3389/fnmol.2018.00012
Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition.
Ahmed Rebekah M,Highton-Williamson Elizabeth,Caga Jashelle,Thornton Nicolette,Ramsey Eleanor,Zoing Margaret,Kim Woojin Scott,Halliday Glenda M,Piguet Olivier,Hodges John R,Farooqi I Sadaf,Kiernan Matthew C
Journal of Alzheimer's disease : JAD
BACKGROUND:Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. OBJECTIVE:This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. METHODS:One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. RESULTS:There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration. CONCLUSION:A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.
10.3233/JAD-170660
Regulation of astrocyte lipid metabolism and ApoE secretionby the microglial oxysterol, 25-hydroxycholesterol.
Journal of lipid research
Neuroinflammation, a major hallmark of Alzheimer's disease and several other neurological and psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol metabolism. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via ApoE-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here, we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. Extracellular levels of ApoE lipoprotein particles increased after treatment of astrocytes with 25HC without an increase in Apoe mRNA expression. In mouse astrocytes-expressing human ApoE3 or ApoE4, 25HC promoted extracellular ApoE3 better than ApoE4. Increased extracellular ApoE was due to elevated efflux from increased Abca1 expression via LXRs as well as decreased lipoprotein reuptake from suppressed Ldlr expression via inhibition of SREBP. 25HC also suppressed expression of Srebf2, but not Srebf1, leading to reduced cholesterol synthesis in astrocytes without affecting fatty acid levels. We further show that 25HC promoted the activity of sterol-o-acyl transferase that led to a doubling of the amount of cholesteryl esters and their concomitant storage in lipid droplets. Our results demonstrate an important role for 25HC in regulating astrocyte lipid metabolism.
10.1016/j.jlr.2023.100350
The shared role of cholesterol in neuronal and peripheral inflammation.
Pharmacology & therapeutics
Neurodegeneration and its loss of cognitive function is associated with inflammation and an accumulation of lipids. In the periphery, cholesterol's uptake drives a major component of chronic inflammation. In this perspective, we describe the cellular and molecular roles of cholesterol in neuroinflammation and contrast them with those in the periphery. Incorporating shared mechanisms from the periphery, cholesterol emerges as a central signal originating in astrocytes and connecting inflammatory escalation in neurons and microglia. A cholesterol uptake pathway is proposed for neuroinflammation, and we speculate on the binding of cholesterol transport protein apolipoprotein E (apoE), including the Christchurch mutant (R136S), to cell surface receptors as a potential protective modality against uptake of astrocyte cholesterol and escalated neuroinflammation. Lastly, we discuss the molecular basis of cholesterol signaling through nanoscopic clustering and peripheral sources of cholesterol after opening of the blood brain barrier.
10.1016/j.pharmthera.2023.108486
Microglia are not necessary for maintenance of blood-brain barrier properties in health, but PLX5622 alters brain endothelial cholesterol metabolism.
Neuron
Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature.
10.1016/j.neuron.2024.07.015
TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.
Nugent Alicia A,Lin Karin,van Lengerich Bettina,Lianoglou Steve,Przybyla Laralynne,Davis Sonnet S,Llapashtica Ceyda,Wang Junhua,Kim Do Jin,Xia Dan,Lucas Anthony,Baskaran Sulochanadevi,Haddick Patrick C G,Lenser Melina,Earr Timothy K,Shi Ju,Dugas Jason C,Andreone Benjamin J,Logan Todd,Solanoy Hilda O,Chen Hang,Srivastava Ankita,Poda Suresh B,Sanchez Pascal E,Watts Ryan J,Sandmann Thomas,Astarita Giuseppe,Lewcock Joseph W,Monroe Kathryn M,Di Paolo Gilbert
Neuron
Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer's disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase is also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding replicates in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it is rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia.
10.1016/j.neuron.2019.12.007
Plant sterols: Friend or foe in CNS disorders?
Vanmierlo Tim,Bogie Jeroen F J,Mailleux Jo,Vanmol Jasmine,Lütjohann Dieter,Mulder Monique,Hendriks Jerome J A
Progress in lipid research
In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders.
10.1016/j.plipres.2015.01.003
Association of blood lipids with onset and prognosis of amyotrophic lateral sclerosis: results from the ALS Swabia registry.
Journal of neurology
BACKGROUND:To date, the role of blood lipid levels and their association with the onset and prognosis of ALS is controversial. We explored these associations in a large, population-based case-control study. METHODS:Between October 2010 and June 2014, 336 ALS patients (mean age 65.7 ± 10.7; 57.7% male) and 487 sex- and age-matched controls from the same geographic region were recruited within the ALS registry in Southwest Germany. Triglycerides and cholesterol (high-density lipoprotein (HDL), low-density lipoprotein (LDL), total) were measured. The ALS cohort was followed up for vital status. Conditional logistic regression models were applied to calculate odds ratio (OR) for risk of ALS associated with serum lipid concentrations. In ALS patients only, survival models were used to appraise the prognostic value. RESULTS:High concentration of total cholesterol (OR 1.60, 95% confidence interval (CI) 1.03-2.49, top vs. bottom quartile), but not HDL, LDL, LDL-HDL ratio, or triglycerides, was positively associated with the risk of ALS. During the median follow-up time of 88.9 months, 291 deaths occurred among 336 ALS patients. In the adjusted survival analysis, higher HDL (HR 1.72, 95% CI 1.19-2.50) and LDL cholesterol levels (HR 1.58, 95% CI 1.11-2.26) were associated with higher mortality in ALS patients. In contrast, higher triglyceride levels were associated with lower mortality (HR 0.68, 95% CI 0.48-0.96). CONCLUSION:The results highlight the importance to distinguish cholesterol from triglycerides when considering the prognostic role of lipid metabolism in ALS. It further strengthens the rationale for a triglyceride-rich diet, while the negative impact of cholesterol must be further explored.
10.1007/s00415-023-11630-4
Genetic variation in targets of lipid-lowering drugs and amyotrophic lateral sclerosis risk: a Mendelian randomization study.
Amyotrophic lateral sclerosis & frontotemporal degeneration
BACKGROUND:The use of lipid-lowering drugs is still highly controversial in patients with amyotrophic lateral sclerosis (ALS). We performed a drug-target Mendelian randomization (MR) analysis to investigate the effect of targeted lipid-lowering drugs on the risk of ALS. METHODS:First, we evaluated the causal relationship between HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase (HMGCR) inhibitors-taking trait and ALS using a bidirectional two-sample MR study. Second, we investigated the causal relationship between lipid-lowering drugs and ALS through a drug-target MR approach. The summary data for HMGCR inhibitors-taking traits were extracted from a genome-wide association study (GWAS) of medication use and associated disease in the UK Biobank. The summary data for low-density lipoprotein cholesterol and apolipoprotein B (apoB) were extracted from a meta-analysis of GWAS in individuals of European ancestry in the UKB. The GWAS summary data of ALS were obtained from the Project MinE. RESULTS:Our bidirectional two-sample MR showed that genetically determined increased HMGCR inhibitors-taking trait was an independent risk factor for ALS (odds ratio [OR] = 1.090, 95% confidence interval [CI] = 1.035-1.150, = 0.001). The results of drug-target MR showed that the increased expression of the gene in blood with the higher risk of ALS (OR = 1.21, 95% CI = 1.01-1.46; = 0.042) through SMR method and the apoB level mediated by the gene increased the risk of ALS (OR = 1.15; 95% CI =1.05-1.25; = 0.001) through inverse-variance weighted MR method. CONCLUSION:This present study provides genetic support for a positive causal effect of HMGCR inhibitors-taking trait and ALS. The reason for this may be due to the underlying disease condition behind the medication, rather than the medication itself. Our findings also suggested that HMGCR and apoB inhibitors may have potential protective effects on ALS.
10.1080/21678421.2023.2255622
Liver X Receptor Genes Variants Modulate ALS Phenotype.
Mouzat Kevin,Molinari Nicolas,Kantar Jovana,Polge Anne,Corcia Philippe,Couratier Philippe,Clavelou Pierre,Juntas-Morales Raul,Pageot Nicolas,Lobaccaro Jean -Marc A,Raoul Cedric,Lumbroso Serge,Camu William
Molecular neurobiology
Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRβ SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.
10.1007/s12035-017-0453-2
Lipid Biomarkers for Amyotrophic Lateral Sclerosis.
González De Aguilar Jose-Luis
Frontiers in neurology
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease primarily characterized by the selective loss of upper and lower motor neurons. To date, there is still an unmet need for robust and practical biomarkers that could estimate the risk of the disease and its progression. Based on metabolic modifications observed at the level of the whole body, different classes of lipids have been proposed as potential biomarkers. This review summarizes investigations carried out over the last decade that focused on changes in three major lipid species, namely cholesterol, triglycerides and fatty acids. Despite some contradictory findings, it is becoming increasingly accepted that dyslipidemia, and related aberrant energy homeostasis, must be considered as essential components of the pathological process. Therefore, it is tempting to envisage dietary interventions as a means to counterbalance the metabolic disturbances and ameliorate the patient's quality of life.
10.3389/fneur.2019.00284
Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects.
Biomedicines
BACKGROUND:Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. METHODS:Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. RESULTS:Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025-1.148, = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013-1.141, = 0.017; after removing: OR = 1.036, 95% CI = 0.949-1.131, = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823-1.296, = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991-1.005, = 0.538) had no association with ALS. CONCLUSIONS:Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention.
10.3390/biomedicines11051359
Central nervous system cholesterol metabolism in health and disease.
IUBMB life
Cholesterol is a ubiquitous and essential component of cellular membranes, as it regulates membrane structure and fluidity. Furthermore, cholesterol serves as a precursor for steroid hormones, oxysterol, and bile acids, that are essential for maintaining many of the body's metabolic processes. The biosynthesis and excretion of cholesterol is tightly regulated in order to maintain homeostasis. Although virtually all cells have the capacity to make cholesterol, the liver and brain are the two main organs producing cholesterol in mammals. Once produced, cholesterol is transported in the form of lipoprotein particles to other cell types and tissues. Upon formation of the blood-brain barrier (BBB) during embryonic development, lipoproteins cannot move between the central nervous system (CNS) and the rest of the body. As such, cholesterol biosynthesis and metabolism in the CNS operate autonomously without input from the circulation system in normal physiological conditions. Nevertheless, similar regulatory mechanisms for maintaining cholesterol homeostasis are utilized in both the CNS and peripheral systems. Here, we discuss the functions and metabolism of cholesterol in the CNS. We further focus on how different CNS cell types contribute to cholesterol metabolism, and how ApoE, the major CNS apolipoprotein, is involved in normal and pathophysiological functions. Understanding these basic mechanisms will aid our ability to elucidate how CNS cholesterol dysmetabolism contributes to neurogenerative diseases.
10.1002/iub.2662
Cholesterol secosterol aldehyde adduction and aggregation of Cu,Zn-superoxide dismutase: Potential implications in ALS.
Redox biology
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. While the fundamental causes of the disease are still unclear, the accumulation of Cu,Zn-superoxide dismutase (SOD1) immunoreactive aggregates is associated with familial ALS cases. Cholesterol 5,6-secosterol aldehydes (Seco A and Seco B) are reported to contribute to neurodegenerative disease pathology by inducing protein modification and aggregation. Here we have investigated the presence of secosterol aldehydes in ALS SOD1-G93A rats and their capacity to induce SOD1 aggregation. Secosterol aldehydes were analyzed in blood plasma, spinal cord and motor cortex of ALS rats at the pre-symptomatic and symptomatic stages. Seco B was significantly increased in plasma of symptomatic ALS rats compared to pre-symptomatic animals, suggesting an association with disease progression. In vitro experiments showed that both Seco A and Seco B induce the formation of high molecular weight (HMW) SOD1 aggregates with amorphous morphology. SOD1 adduction to ω-alkynyl-secosterols analyzed by click assay showed that modified proteins are only detected in the HMW region, indicating that secosterol adduction generates species highly prone to aggregate. Of note, SOD1-secosterol adducts containing up to five secosterol molecules were confirmed by MALDI-TOF analysis. Interestingly, mass spectrometry sequencing of SOD1 aggregates revealed preferential secosterol adduction to Lys residues located at the electrostatic loop (Lys 122, 128 and 136) and nearby the dimer interface (Lys 3 and 9). Altogether, our results show that secosterol aldehydes are increased in plasma of symptomatic ALS rats and represent a class of aldehydes that can potentially modify SOD1 enhancing its propensity to aggregate.
10.1016/j.redox.2018.08.007
Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study.
Journal of neurology
BACKGROUND:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. METHODS:A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. RESULTS:Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HR = 1.07, 95%CI:1.02-1.12; =18%) and lower HDL-c (HR = 0.83, 95%CI:0.74-0.94; =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (OR = 1.085, 95%:CI 1.008-1.168, p = 0.0406), total cholesterol (OR = 1.081, 95%:CI 1.013-1.154, p = 0.0458) and apolipoprotein B (OR = 1.104, 95%:CI 1.041-1.171, p = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (OR = 1.424, 95%CI 1.072-1.829, p = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (OR = 0.84, 95%CI 0.759-0.929, p = 0.00275) and FTD risk (OR = 0.581, 95%CI 0.387-0.874, p = 0.0362). CONCLUSION:These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.
10.1007/s00415-024-12665-x
A decrease in blood cholesterol after gastrostomy could impact survival in ALS.
Blasco H,Patin F,Molinier S,Vourc'h P,Le Tilly O,Bakkouche S,Andres C R,Meininger V,Couratier P,Corcia P
European journal of clinical nutrition
Although the global benefits of gastrostomy have been proven in amyotrophic lateral sclerosis (ALS), the impact on biological parameters has not been explored yet. The aim of this preliminary work was to evaluate the modification of biological parameters in patients with ALS undergoing gastrostomy. We retrospectively collected clinical and biological data from 44 patients having undergone gastrostomy at three time points (T0, T1 and T2: before, at the time of and after gastrostomy). We examined the relationship between the biological parameters and disease progression. Variations of the concentrations of total cholesterol significantly differed before (T1-T0) vs those after gastrostomy (T2-T1; P=0.0044). The variations of total cholesterol and low-density lipoprotein cholesterol concentrations after gastrostomy were negatively associated with survival (P=0.0002). This study showed for the first time that patients with ALS fed quite exclusively by gastrostomy had decreased blood cholesterol after gastrostomy. We suggest that a restoration of normal lipid metabolism should be planned in patients with ALS.
10.1038/ejcn.2017.54
TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2.
Scientific reports
Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia.
10.1038/s41598-022-12133-4
Liver X receptors: from cholesterol regulation to neuroprotection-a new barrier against neurodegeneration in amyotrophic lateral sclerosis?
Cellular and molecular life sciences : CMLS
Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3 years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy.
10.1007/s00018-016-2330-y
Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?
International journal of molecular sciences
Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients.
10.3390/ijms20163858
Defective cholesterol metabolism in amyotrophic lateral sclerosis.
Abdel-Khalik Jonas,Yutuc Eylan,Crick Peter J,Gustafsson Jan-Åke,Warner Margaret,Roman Gustavo,Talbot Kevin,Gray Elizabeth,Griffiths William J,Turner Martin R,Wang Yuqin
Journal of lipid research
As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid.
10.1194/jlr.P071639
Cholesterol, oxysterol, triglyceride, and coenzyme Q homeostasis in ALS. Evidence against the hypothesis that elevated 27-hydroxycholesterol is a pathogenic factor.
Wuolikainen Anna,Acimovic Jure,Lövgren-Sandblom Anita,Parini Paolo,Andersen Peter M,Björkhem Ingemar
PloS one
High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time. The gene encoding cholesterol 27-hydroxylase, CYP27A1, was recently identified as a susceptibility gene for sporadic ALS. A product of this enzyme is 27-hydroxycholesterol. We investigated plasma samples from 52 ALS patients and 40 control subjects (spouses) regarding cholesterol homeostasis, lipid profiles, and coenzyme Q. Eleven of the patients carried mutations in C9orf72 and seven in SOD1. Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls. It was not possible to link the reduced levels to any specific mutation, and there was no significant correlation between 27-hydroxycholesterol and survival. With normalization for diet using the spouses, a correlation was found between survival and total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and coenzyme Q. We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.
10.1371/journal.pone.0113619
The role of statins in amyotrophic lateral sclerosis: protective or not?
Frontiers in neuroscience
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.
10.3389/fnins.2024.1422912
Lipids and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.
European journal of neurology
OBJECTIVE:Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis. METHODS:Using genome-wide association study summary-level data for total cholesterol (TC) (n = 188,578), high-density lipoprotein cholesterol (HDL-C) (n = 403,943), low-density lipoprotein cholesterol (LDL-C) (n = 440,546), apolipoprotein A1 (ApoA1) (n = 391,193), apolipoprotein B (ApoB) (n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL-C is a potential mediator on the pathway from traits of LDL-C-related polyunsaturated fatty acids (PUFAs) to ALS risk. RESULTS:We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL-C had the most potent effect (OR 1.028, 95% CI 1.008-1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL-C-modifying lifestyles and ALS. The mediation analysis revealed that LDL-C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009. CONCLUSIONS:We provided high-level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL-C in the pathway from PUFAs to ALS.
10.1111/ene.15810
Ferritin and LDL-cholesterol as biomarkers of fat-free mass loss in ALS.
Jésus Pierre,Blasco Hélène,Patin Franck,Bakkouche Salah Eddine,Beltran Stéphane,Andrés Christian R,Vourc'h Patrick,Maillot François,Corcia Philippe
Amyotrophic lateral sclerosis & frontotemporal degeneration
The availability of longitudinal clinical and biological data led us to wonder whether these parameters could be used to predict disturbances in body composition during ALS progression. Bioelectrical impedance analysis (BIA), as well as clinical and biological parameters (blood lipids and ferritin), were collected one year after diagnosis in ALS patients. The correlations were evaluated by the Spearman test. Performances to predict the evolution of BIA parameters during ALS evolution were evaluated by ROC analysis. Forty-two ALS patients were enrolled. Variations in FFM over one year were correlated to the variations in LDL-cholesterol ( = 0.53, = 0.002) and ferritin ( = -0.58, = 0.0002). To predict FFM loss, an increase in ferritin over 9 µg/L had a sensitivity of 90.0% and a specificity of 80.0% ( < 0.0001). Ferritine evolution would allow to easily follow the FFM without BIA during ALS. In addition, an adapted nutritional treatment based on this biological parameter might slow down ALS progression.
10.1080/21678421.2019.1597126
Premorbid lipid levels and long-term risk of ALS-a population-based cohort study.
Amyotrophic lateral sclerosis & frontotemporal degeneration
OBJECTIVE:To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk. METHODS:From Norwegian cardiovascular health surveys (1974-2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models. RESULTS:Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01-1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6-7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results. CONCLUSIONS:Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.
10.1080/21678421.2023.2295455
Cholesterol Metabolism in the Brain and Its Association with Parkinson's Disease.
Jin Uram,Park Soo Jin,Park Sang Myun
Experimental neurobiology
Parkinson's disease (PD) is the second most progressive neurodegenerative disorder of the aging population after Alzheimer's disease (AD). Defects in the lysosomal systems and mitochondria have been suspected to cause the pathogenesis of PD. Nevertheless, the pathogenesis of PD remains obscure. Abnormal cholesterol metabolism is linked to numerous disorders, including atherosclerosis. The brain contains the highest level of cholesterol in the body and abnormal cholesterol metabolism links also many neurodegenerative disorders such as AD, PD, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The blood brain barrier effectively prevents uptake of lipoprotein-bound cholesterol from blood circulation. Accordingly, cholesterol level in the brain is independent from that in peripheral tissues. Because cholesterol metabolism in both peripheral tissue and the brain are quite different, cholesterol metabolism associated with neurodegeneration should be examined separately from that in peripheral tissues. Here, we review and compare cholesterol metabolism in the brain and peripheral tissues. Furthermore, the relationship between alterations in cholesterol metabolism and PD pathogenesis is reviewed.
10.5607/en.2019.28.5.554
Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon?
The FEBS journal
Amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease, is characterized by the selective degeneration of motor neurons leading to paralysis and eventual death. Multiple pathogenic mechanisms, including systemic dysmetabolism, have been proposed to contribute to ALS. Among them, dyslipidemia, i.e., abnormal level of cholesterol and other lipids in the circulation and central nervous system (CNS), has been reported in ALS patients, but without a consensus. Cholesterol is a constituent of cellular membranes and a precursor of steroid hormones, oxysterols, and bile acids. Consequently, optimal cholesterol levels are essential for health. Due to the blood-brain barrier (BBB), cholesterol cannot move between the CNS and the rest of the body. As such, cholesterol metabolism in the CNS is proposed to operate autonomously. Despite its importance, it remains elusive how cholesterol dyshomeostasis may contribute to ALS. In this review, we aim to describe the current state of cholesterol metabolism research in ALS, identify unresolved issues, and provide potential directions.
10.1111/febs.16175
Dysregulation of muscle cholesterol transport in amyotrophic lateral sclerosis.
Brain : a journal of neurology
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, with a typical lifespan of 3-5 years. Altered metabolism is a key feature of ALS that strongly influences prognosis, with an increase in whole-body energy expenditure and changes in skeletal muscle metabolism, including greater reliance on fat oxidation. Dyslipidemia has been described in ALS as part of the metabolic dysregulation, but its role in the pathophysiology of the disease remains controversial. Among the lipids, cholesterol is of particular interest as a vital component of cell membranes, playing a key role in signal transduction and mitochondrial function in muscle. The aim of this study was to investigate whether motor dysfunction in ALS might be associated with dysregulation of muscle cholesterol metabolism. We determined cholesterol content and analyzed the expression of key determinants of the cholesterol metabolism pathway in muscle biopsies from thirteen ALS patients and ten asymptomatic ALS-mutation gene carriers compared to sixteen controls. Using human control primary myotubes, we further investigated the potential contribution of cholesterol dyshomeostasis to reliance on mitochondrial fatty acid. We found that cholesterol accumulates in the skeletal muscle of ALS patients and that cholesterol overload significantly correlates with disease severity evaluated by the Revised ALS Functional Rating Scale. These defects are associated with overexpression of the genes of the lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2), which are required for cholesterol transfer from late endosomes/lysosomes to cellular membranes. Most notably, a significant increase in NPC2 mRNA levels could be detected in muscle samples from asymptomatic ALS-mutation carriers, long before disease onset. We found that filipin-stained unesterified cholesterol accumulated in the lysosomal compartment in ALS muscle samples, suggesting dysfunction of the NPC1/2 system. Accordingly, we report here that experimental NPC1 inhibition or lysosomal pH alteration in human primary myotubes was sufficient to induce the overexpression of NPC1 and NPC2 mRNA. Finally, acute NPC1 inhibition in human control myotubes induced a shift towards a preferential use of fatty acids, thus reproducing the metabolic defect characteristic of ALS muscle. We conclude that cholesterol homeostasis is dysregulated in ALS muscle from the presymptomatic stage. Targeting NPC1/2 dysfunction may be a new therapeutic strategy for ALS to restore muscle energy metabolism and slow motor symptom progression.
10.1093/brain/awae270
Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.
Science translational medicine
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
10.1126/scitranslmed.abj0264