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Neuron Feb 2024Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the...
Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
Topics: Mice; Animals; Apolipoprotein E4; Apolipoprotein E3; Apolipoproteins E; Tauopathies; Cholesterol; Alzheimer Disease; Mice, Transgenic
PubMed: 37995685
DOI: 10.1016/j.neuron.2023.10.023 -
Trends in Endocrinology and Metabolism:... Aug 2023Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E... (Review)
Review
Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.
Topics: Humans; Neurodegenerative Diseases; Lipid Metabolism; Apolipoproteins E; Phenotype; Alzheimer Disease
PubMed: 37357100
DOI: 10.1016/j.tem.2023.05.002 -
European Heart Journal Jul 2023Due to growing environmental focus, plant-based diets are increasing steadily in popularity. Uncovering the effect on well-established risk factors for cardiovascular... (Meta-Analysis)
Meta-Analysis
AIMS
Due to growing environmental focus, plant-based diets are increasing steadily in popularity. Uncovering the effect on well-established risk factors for cardiovascular diseases, the leading cause of death worldwide, is thus highly relevant. Therefore, a systematic review and meta-analysis were conducted to estimate the effect of vegetarian and vegan diets on blood levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B.
METHODS AND RESULTS
Studies published between 1980 and October 2022 were searched for using PubMed, Embase, and references of previous reviews. Included studies were randomized controlled trials that quantified the effect of vegetarian or vegan diets vs. an omnivorous diet on blood lipids and lipoprotein levels in adults over 18 years. Estimates were calculated using a random-effects model. Thirty trials were included in the study. Compared with the omnivorous group, the plant-based diets reduced total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B levels with mean differences of -0.34 mmol/L (95% confidence interval, -0.44, -0.23; P = 1 × 10-9), -0.30 mmol/L (-0.40, -0.19; P = 4 × 10-8), and -12.92 mg/dL (-22.63, -3.20; P = 0.01), respectively. The effect sizes were similar across age, continent, duration of study, health status, intervention diet, intervention program, and study design. No significant difference was observed for triglyceride levels.
CONCLUSION
Vegetarian and vegan diets were associated with reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B-effects that were consistent across various study and participant characteristics. Plant-based diets have the potential to lessen the atherosclerotic burden from atherogenic lipoproteins and thereby reduce the risk of cardiovascular disease.
Topics: Adult; Humans; Diet, Vegan; Diet, Vegetarian; Randomized Controlled Trials as Topic; Lipids; Vegetarians; Cholesterol, LDL; Lipoproteins; Cardiovascular Diseases; Atherosclerosis; Apolipoproteins
PubMed: 37226630
DOI: 10.1093/eurheartj/ehad211 -
Immunity Jan 2024The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune...
The dominant risk factors for late-onset Alzheimer's disease (AD) are advanced age and the APOE4 genetic variant. To examine how these factors alter neuroimmune function, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing the three common human APOE alleles. Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency increased with age and APOE4 burden. An analogous population was detectable in the brains of human AD patients, including in the cortical tissue, using multiplexed spatial transcriptomics. This population, which we designate as terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and altered cell-cell communication during aducanumab treatment. TIM may represent an exhausted-like state for inflammatory microglia in the AD milieu that contributes to AD risk and pathology in APOE4 carriers and the elderly, thus presenting a potential therapeutic target for AD.
Topics: Aged; Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Brain; Genotype; Microglia
PubMed: 38159571
DOI: 10.1016/j.immuni.2023.12.001 -
Trends in Cell Biology Apr 2024Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude... (Review)
Review
Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.
Topics: Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Astrocytes; Brain; Neurodegenerative Diseases
PubMed: 37805344
DOI: 10.1016/j.tcb.2023.09.004 -
International Journal of Molecular... Sep 2023Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease,... (Review)
Review
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
Topics: Adult; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Apoprotein(a); Lipoprotein(a); Apolipoproteins A; Hyperlipoproteinemias; Aortic Valve Stenosis
PubMed: 37686428
DOI: 10.3390/ijms241713622 -
European Journal of Preventive... Sep 2023Studies have linked gut microbiome and heart failure (HF). However, their causal relationships and potential mediating factors have not been well defined. To investigate... (Meta-Analysis)
Meta-Analysis
AIMS
Studies have linked gut microbiome and heart failure (HF). However, their causal relationships and potential mediating factors have not been well defined. To investigate the causal relationships between the gut microbiome and HF and the mediating effect of potential blood lipids by using genetics.
METHODS AND RESULTS
We performed a bidirectional and mediation Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of gut microbial taxa (Dutch Microbiome Project, n = 7738), blood lipids (UK Biobank, n = 115 078), and a meta-analysis of HF (115 150 cases and 1550 331 controls). We applied the inverse-variance weighted estimation method as the primary method, with several other estimators as complementary methods. The multivariable MR approach based on Bayesian model averaging (MR-BMA) was used to prioritize the most likely causal lipids. Six microbial taxa are suggestively associated with HF causally. The most significant taxon was the species Bacteroides dorei [odds ratio = 1.059, 95% confidence interval (CI) = 1.022-1.097, P-value = 0.0017]. The MR-BMA analysis showed that apolipoprotein B (ApoB) was the most likely causal lipid for HF (the marginal inclusion probability = 0.717, P-value = 0.005). The mediation MR analysis showed that ApoB mediated the causal effects of species B. dorei on HF (proportion mediated = 10.1%, 95% CI = 0.2-21.6%, P-value = 0.031).
CONCLUSION
The study suggested a causal relationship between specific gut microbial taxa and HF and that ApoB might mediate this relationship as the primary lipid determinant of HF.
Topics: Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Bayes Theorem; Genome-Wide Association Study; Heart Failure; Apolipoproteins B; Lipids; Polymorphism, Single Nucleotide
PubMed: 37195998
DOI: 10.1093/eurjpc/zwad171 -
Cellular and Molecular Neurobiology Oct 2023The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological... (Review)
Review
The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing β-amyloid (Aβ) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aβ pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aβ deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.
Topics: Humans; Alzheimer Disease; Apolipoprotein E4; Amyloid beta-Peptides; Apolipoproteins E; Brain
PubMed: 37227619
DOI: 10.1007/s10571-023-01365-1 -
Nature Neuroscience Dec 2023Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating...
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
Topics: Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E3; Apolipoprotein E4; Mutation; Neuroinflammatory Diseases; Tauopathies
PubMed: 37957317
DOI: 10.1038/s41593-023-01480-8 -
Journal of the American Society of... Nov 2023African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant,... (Meta-Analysis)
Meta-Analysis
SIGNIFICANCE STATEMENT
African Americans are at increased risk of CKD in part due to high-risk (HR) variants in the apolipoprotein L1 ( APOL1 ) gene, termed G1/G2. A different APOL1 variant, p.N264K , reduced the risk of CKD and ESKD among carriers of APOL1 HR variants to levels comparable with individuals with APOL1 low-risk variants in an analysis of 121,492 participants of African ancestry from the Million Veteran Program (MVP). Functional genetic studies in cell models showed that APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR mutations. Pharmacologic inhibitors that mimic this mutation blocking APOL1 -mediated pore formation may be able to prevent and/or treat APOL1 -associated kidney disease.
BACKGROUND
African Americans are at increased risk for nondiabetic CKD in part due to HR variants in the APOL1 gene.
METHODS
We tested whether a different APOL1 variant, p.N264K , modified the association between APOL1 HR genotypes (two copies of G1/G2) and CKD in a cross-sectional analysis of 121,492 participants of African ancestry from the MVP. We replicated our findings in the Vanderbilt University Biobank ( n =14,386) and National Institutes of Health All of Us ( n =14,704). Primary outcome was CKD and secondary outcome was ESKD among nondiabetic patients. Primary analysis compared APOL1 HR genotypes with and without p.N264K . Secondary analyses included APOL1 low-risk genotypes and tested for interaction. In MVP, we performed sequential logistic regression models adjusting for demographics, comorbidities, medications, and ten principal components of ancestry. Functional genomic studies expressed APOL1 HR variants with and without APOL1 p.N264K in cell models.
RESULTS
In the MVP cohort, 15,604 (12.8%) had two APOL1 HR variants, of which 582 (0.5%) also had APOL1 p.N264K . In MVP, 18,831 (15%) had CKD, 4177 (3%) had ESKD, and 34% had diabetes. MVP APOL1 HR, without p.N264K , was associated with increased odds of CKD (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.60 to 1.85) and ESKD (OR, 3.94; 95% CI, 3.52 to 4.41). In MVP, APOL1 p.N264K mitigated the renal risk of APOL1 HR, in CKD (OR, 0.43; 95% CI, 0.28 to 0.65) and ESKD (OR, 0.19; CI 0.07 to 0.51). In the replication cohorts meta-analysis, APOL1 p.N264K mitigated the renal risk of APOL1 HR in CKD (OR, 0.40; 95% CI, 0.18 to 0.92) and ESKD (OR, 0.19; 95% CI, 0.05 to 0.79). In the mechanistic studies, APOL1 p.N264K blocked APOL1 pore-forming function and ion channel conduction and reduced toxicity of APOL1 HR variants.
CONCLUSIONS
APOL1 p.N264K is associated with reduced risk of CKD and ESKD among carriers of APOL1 HR to levels comparable with individuals with APOL1 low-risk genotypes.
Topics: Humans; Apolipoprotein L1; Apolipoproteins; Cross-Sectional Studies; Genetic Predisposition to Disease; Genotype; Ion Channels; Population Health; Renal Insufficiency, Chronic; Black or African American
PubMed: 37798822
DOI: 10.1681/ASN.0000000000000219