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Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer's disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE's role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism. [ABSTRACT FROM AUTHOR]

Apolipoprotein E4 (ApoE4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer's disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in ApoE4 carriers, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant APOE4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, our study demonstrates that ApoE4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Three common isoforms of the apolipoprotein E (APOE) gene - APOE2, APOE3, and APOE4 - hold varying significance in Alzheimer's Disease (AD) risk. The APOE4 allele is the strongest known genetic risk factor for late-onset Alzheimer's Disease (AD), and its expression has been shown to correlate with increased central nervous system (CNS) amyloid deposition and accelerated neurodegeneration. Conversely, APOE2 is associated with reduced AD risk and lower CNS amyloid burden. Recent clinical data have suggested that increased blood-brain barrier (BBB) leakage is commonly observed among AD patients and APOE4 carriers. However, it remains unclear how different APOE isoforms may impact AD-related pathologies at the BBB. Methods: To explore potential impacts of APOE genotypes on BBB properties and BBB interactions with amyloid beta, we differentiated isogenic human induced pluripotent stem cell (iPSC) lines with different APOE genotypes into both brain microvascular endothelial cell-like cells (BMEC-like cells) and brain pericyte-like cells. We then compared the effect of different APOE isoforms on BBB-related and AD-related phenotypes. Statistical significance was determined via ANOVA with Tukey's post hoc testing as appropriate. Results: Isogenic BMEC-like cells with different APOE genotypes had similar trans-endothelial electrical resistance, tight junction integrity and efflux transporter gene expression. However, recombinant APOE4 protein significantly impeded the "brain-to-blood" amyloid beta 1–40 (Aβ40) transport capabilities of BMEC-like cells, suggesting a role in diminished amyloid clearance. Conversely, APOE2 increased amyloid beta 1–42 (Aβ42) transport in the model. Furthermore, we demonstrated that APOE-mediated amyloid transport by BMEC-like cells is dependent on LRP1 and p-glycoprotein pathways, mirroring in vivo findings. Pericyte-like cells exhibited similar APOE secretion levels across genotypes, yet APOE4 pericyte-like cells showed heightened extracellular amyloid deposition, while APOE2 pericyte-like cells displayed the least amyloid deposition, an observation in line with vascular pathologies in AD patients. Conclusions: While APOE genotype did not directly impact general BMEC or pericyte properties, APOE4 exacerbated amyloid clearance and deposition at the model BBB. Conversely, APOE2 demonstrated a potentially protective role by increasing amyloid transport and decreasing deposition. Our findings highlight that iPSC-derived BBB models can potentially capture amyloid pathologies at the BBB, motivating further development of such in vitro models in AD modeling and drug development. [ABSTRACT FROM AUTHOR]

Alzheimer's disease involves environmental influences and genetic and biochemical factors that lead to the build up of harmful proteins like amyloid and neurofibrillary tangles in brain. This accumulation can disturb the communication between nerve cells. Result in cognitive difficulties. This analysis emphasizes the importance of elements like air pollution and toxic metals in addition to discussing the influence of inflammation oxygen related stress and antioxidants, on disease progression. It also explores how specific hormones and enzymes influence the course of the disease. Alzheimer’s stands out as a condition that leads to cognitive decline and affects nerve tissues in the brain extensively. It is identified through the development of tangles and the buildup of amyloid proteins outside cells that form plaques hindering communication among neurons. This inherited degenerative condition affects nerve function and results in a decrease, in abilities and memory loss. This review delves into biochemical pathways associated with Alzheimers disease; discussing the impact of air pollution and harmful metals along with inflammation and oxidative stress as well as the influence of antioxidants and certain hormones such as insulin and proteins like GO and insulin like growth factor (IGF) along with leptin in the process. It also touches upon the significance of enzymes like choline acetyltransferase and essential proteins in the disease pathway such, as C reactive protein interleukins and E methione. This research is crucial for gaining insights into the processes involved in Alzheimers disease and could help in crafting better prevention and treatment approaches, down the line.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Human apolipoprotein E (ApoE) was first identified as a polymorphic gene in the 1970s; however, the genetic association of ApoE genotypes with late-onset sporadic Alzheimer's disease (sAD) was only discovered 20 years later. Since then, intensive research has been undertaken to understand the molecular effects of ApoE in the development of sAD. Despite three decades' worth of effort and over 10,000 papers published, the greatest mystery in the ApoE field remains: human ApoE isoforms differ by only one or two amino acid residues; what is responsible for their significantly distinct roles in the etiology of sAD, with ApoE4 conferring the greatest genetic risk for sAD whereas ApoE2 providing exceptional neuroprotection against sAD. Emerging research starts to point to a novel and compelling hypothesis that the sialoglycans posttranslationally appended to human ApoE may serve as a critical structural modifier that alters the biology of ApoE, leading to the opposing impacts of ApoE isoforms on sAD and likely in the peripheral systems as well. ApoE has been shown to be posttranslationally glycosylated in a species-, tissue-, and cell-specific manner. Human ApoE, particularly in brain tissue and cerebrospinal fluid (CSF), is highly glycosylated, and the glycan chains are exclusively attached via an O-linkage to serine or threonine residues. Moreover, studies have indicated that human ApoE glycans undergo sialic acid modification or sialylation, a structural alteration found to be more prominent in ApoE derived from the brain and CSF than plasma. However, whether the sialylation modification of human ApoE has a biological role is largely unexplored. Our group recently first reported that the three major isoforms of human ApoE in the brain undergo varying degrees of sialylation, with ApoE2 exhibiting the most abundant sialic acid modification, whereas ApoE4 is the least sialylated. Our findings further indicate that the sialic acid moiety on human ApoE glycans may serve as a critical modulator of the interaction of ApoE with amyloid β (Aβ) and downstream Aβ pathogenesis, a prominent pathologic feature in AD. In this review, we seek to provide a comprehensive summary of this exciting and rapidly evolving area of ApoE research, including the current state of knowledge and opportunities for future exploration. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is primarily expressed and secreted by the liver. The hormone is crucial for regulation of glucose homeostasis, lipid metabolism, and energy balance. Compared with natural FGF21, FGF21 analogs have become drug candidates for the treatment of cardiovascular and metabolic diseases owing to their long half-life and greater stability in vitro. Apolipoprotein E (Apoe)-knockout (Apoe-/-) mice exhibit progressive disruptions in lipid metabolism in vivo and develop further atherosclerosis pathological features owing to Apoe deletion. Therefore, this study used an Apoe-/- mouse model to investigate the effects of a long- acting FGF21 analog (PF-05231023) on lipidmetabolism and related parameters. Eighteen Apoe-/- female mice were fed a Western diet equivalent for 12 weeks, and then randomly assigned to intraperitoneally receive either physiological saline (the control group) or 10 mg/kg PF-05231023 (the treatment group) three times a week for seven consecutive weeks. Body composition, glucose tolerance, blood and liver cholesterol, triglyceride levels, liver vacuolization levels, peri-ovarian white adipocyte hypertrophy, aortic atherosclerotic plaque formation, and the expression of genes related to lipid metabolism in adipose tissue were subsequently assessed before and after treatment. The aortic atherosclerotic plaque area was reduced in mice in the PF-05231023 treatment group compared with that in the saline group. Although the effect of PF-05231023 on the plasma biochemical indexes of mice was small, it significantly reduced lipid levels and lipid droplet accumulation in the liver, and reduced adipocyte hypertrophy in white adipose tissue. Transcriptome analysis of adipose tissue showed that PF-05231023 treatment downregulated the expression of lipid synthesis-related genes and inhibited the sterol regulatory element binding transcription factor 1 gene, thereby improving lipid deposition. PF-05231023 effectively improved the lipid metabolism of Apoe-/- mice, demonstrating an anti-atherosclerotic effect and providing a scientific basis and experimental foundation for the clinical treatment of cardiovascular diseases by using long- acting FGF21 analogs. [ABSTRACT FROM AUTHOR]

Transmembrane and coiled‐coil 2 (TMCC2) is a human orthologue of the Drosophila gene dementin, mutant alleles of which cause neurodegeneration with features of Alzheimer's disease (AD). TMCC2 and Dementin further have an evolutionarily conserved interaction with the amyloid protein precursor (APP), a protein central to AD pathogenesis. To investigate if human TMCC2 might also participate in mechanisms of neurodegeneration, we examined TMCC2 expression in late onset AD human brain and age‐matched controls, familial AD cases bearing a mutation in APP Val717, and Down syndrome AD. Consistent with previous observations of complex formation between TMCC2 and APP in the rat brain, the dual immunocytochemistry of control human temporal cortex showed highly similar distributions of TMCC2 and APP. In late onset AD cases stratified by APOE genotype, TMCC2 immunoreactivity was associated with dense core senile plaques and adjacent neuronal dystrophies, but not with Aβ surrounding the core, diffuse Aβ plaques or tauopathy. In Down syndrome AD, we observed in addition TMCC2‐immunoreactive and methoxy‐X04‐positive pathological features that were morphologically distinct from those seen in the late onset and familial AD cases, suggesting enhanced pathological alteration of TMCC2 in Down syndrome AD. At the protein level, western blots of human brain extracts revealed that human brain‐derived TMCC2 exists as at least three isoforms, the relative abundance of which varied between the temporal gyrus and cerebellum and was influenced by APOE and/or dementia status. Our findings thus implicate human TMCC2 in AD via its interactions with APP, its association with dense core plaques, as well as its alteration in Down syndrome AD. [ABSTRACT FROM AUTHOR]

The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer's disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in the brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE. However, the distinct roles of the three APOE isoforms in neuronal energy homeostasis remain poorly understood. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4, or carrying an APOE knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3, and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells, indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism. [ABSTRACT FROM AUTHOR]

Background: Individuals with Alzheimer's disease (AD) often require many medications; however, these medications are dosed using regimens recommended for individuals without AD. This is despite reduced abundance and function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in AD, which can impact brain exposure of drugs. The fundamental mechanisms leading to reduced P-gp abundance in sporadic AD remain unknown; however, it is known that the apolipoprotein E (apoE) gene has the strongest genetic link to sporadic AD development, and apoE isoforms can differentially alter BBB function. The aim of this study was to assess if apoE affects P-gp abundance and function in an isoform-dependent manner using a human cerebral microvascular endothelial cell (hCMEC/D3) model. Methods: This study assessed the impact of apoE isoforms on P-gp abundance (by western blot) and function (by rhodamine 123 (R123) uptake) in hCMEC/D3 cells. Cells were exposed to recombinant apoE3 and apoE4 at 2 – 10 µg/mL over 24 – 72 hours. hCMEC/D3 cells were also exposed for 72 hours to astrocyte-conditioned media (ACM) from astrocytes expressing humanised apoE isoforms. Results: P-gp abundance in hCMEC/D3 cells was not altered by recombinant apoE4 relative to recombinant apoE3, nor did ACM containing human apoE isoforms alter P-gp abundance. R123 accumulation in hCMEC/D3 cells was also unchanged with recombinant apoE isoform treatments, suggesting no change to P-gp function, despite both abundance and function being altered by positive controls SR12813 (5 µM) and PSC 833 (5 µM), respectively. Conclusions: Different apoE isoforms have no direct influence on P-gp abundance or function within this model, and further in vivo studies would be required to address whether P-gp abundance or function are reduced in sporadic AD in an apoE isoform-specific manner. [ABSTRACT FROM AUTHOR]

Background: Medications used to treat acute lymphoblastic leukemia (ALL), such as l-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. Procedure: We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. Results: The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). Conclusions: Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings. [ABSTRACT FROM AUTHOR]

Background: This study examines the association between apolipoprotein E (APOE) genotypes and metabolic syndrome (MetS) in an older urban population in South India, as part of the Tata Longitudinal Study on Aging. Methods: A total of 618 participants aged 45 and above were analyzed cross-sectionally for the association between APOE carrier status and MetS (based on both NCEP ATP III and Consensus criteria). Results: Despite the high prevalence of MetS observed in this cohort (51.62 % by NCEP-ATP III and 61.33 % by Consensus criteria), multivariable logistic regression revealed no significant association between APOE genotypes and MetS under both criteria. However, specific associations were noted in age and sex-stratified analyses; notably, E2 carriers under 60 showed 0.42-fold decreased odds (95%CI:0.20,0.89, p-value-0.023) for an increased waist circumference, and E4 carriers above 60 were at 1.85 times increased odds (95 % CI:1.04,3.28, p-value

Abstract Obesity is a metabolic disorder characterized by the hypertrophy expansion of adipose tissue, resulting in dysregulated energy metabolism, and accompanied by chronic low-grade inflammation. Adipose tissue macrophages (ATMs), a principal component of inflammation, respond to microenvironment signals and modulate adipose tissue remodeling and metabolic processes situation-specific. However, the mechanisms governing how the organism maintains equilibrium between its chronic inflammation and metabolism still need to be understood. Here, we describe a novel role of apolipoprotein E (ApoE), which associated with lipid particles, in maintaining fat deposition and system metabolic inflammation. Using human samples and mouse models, we show that ApoE is robustly downregulated in obese individuals, db/db mice, and mice of high-fat diet (HFD) feeding and increased in obese subjects with diabetes. Furthermore, we found that ApoE deficiency mice globally prevented obesity by restraining adipose tissue expansion and improved systemic glucose tolerance and insulin sensitivity. However, macrophage contributed to metabolic inflammation due to increased IL-1β production in adipose tissue from ApoE-/- mice induced by HFD. Our results suggest that the role of ApoE in regulating obesity and obesity-associated glucose dysregulation is inconsistent. Mechanistically, ApoE modulates of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome priming and activation step. Thus, our studies might provide new sights into ApoE, which is required for obesity-induced hyperglycemia, hyperinsulinism, and adaptive inflammation responses but diminishes the tolerance towards a subsequent metabolic inflammatory challenge. Our study shed new light on the integral role of apolipoprotein APOE in immunometabolism and adipose tissue homeostasis.

The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer’s disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in the brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE. However, the distinct roles of the three APOE isoforms in neuronal energy homeostasis remain poorly understood. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4, or carrying an APOE knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3, and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells, indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism.

Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD. Lipid extracts of plasma from active-duty soldiers deployed to the Iraq/Afghanistan wars (control?=?52, mTBI?=?21, PTSD?=?34, and TBI + PTSD?=?13) were subjected to liquid chromatography/mass spectrometry analysis to examine oxylipins and ethanolamides. Linear regression analyses followed by post hoc comparisons were performed to assess the association of these lipids with diagnostic classifications. Significant differences were found in oxylipins derived from arachidonic acid (AA) between controls and mTBI, PTSD, and mTBI + PTSD groups. Levels of AA-derived oxylipins through the cytochrome P450 pathways and anandamide were significantly elevated among mTBI + PTSD patients who were carriers of the apolipoprotein E E4 allele. These studies demonstrate that AA-derived oxylipins and anandamide may be unique blood biomarkers of PTSD and mTBI + PTSD. Further, these AA metabolites may be indicative of an underlying inflammatory process that warrants further investigation. Future validation studies in larger cohorts are required to determine a potential application of this approach in providing a differential diagnosis of mTBI and PTSD in a clinical setting.

Obesity is a metabolic disorder characterized by the hypertrophy expansion of adipose tissue, resulting in dysregulated energy metabolism, and accompanied by chronic low-grade inflammation. Adipose tissue macrophages (ATMs), a principal component of inflammation, respond to microenvironment signals and modulate adipose tissue remodeling and metabolic processes situation-specific. However, the mechanisms governing how the organism maintains equilibrium between its chronic inflammation and metabolism still need to be understood. Here, we describe a novel role of apolipoprotein E (ApoE), which associated with lipid particles, in maintaining fat deposition and system metabolic inflammation. Using human samples and mouse models, we show that ApoE is robustly downregulated in obese individuals, db/db mice, and mice of high-fat diet (HFD) feeding and increased in obese subjects with diabetes. Furthermore, we found that ApoE deficiency mice globally prevented obesity by restraining adipose tissue expansion and improved systemic glucose tolerance and insulin sensitivity. However, macrophage contributed to metabolic inflammation due to increased IL-1β production in adipose tissue from ApoE-/- mice induced by HFD. Our results suggest that the role of ApoE in regulating obesity and obesity-associated glucose dysregulation is inconsistent. Mechanistically, ApoE modulates of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome priming and activation step. Thus, our studies might provide new sights into ApoE, which is required for obesity-induced hyperglycemia, hyperinsulinism, and adaptive inflammation responses but diminishes the tolerance towards a subsequent metabolic inflammatory challenge. Our study shed new light on the integral role of apolipoprotein APOE in immunometabolism and adipose tissue homeostasis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid‐targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid‐positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non‐carriers. Carrier and non‐carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS‐Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non‐carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non‐carriers to amyloid‐targeting therapies and similar or less disease progression with placebo in amyloid‐positive trials. HIGHLIGHTS: Amyloid‐targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers.Clinical decline is the same/slightly faster in amyloid‐positive APOE ε4 non‐carriers.Prevalence of non‐carriers in trial populations could impact outcomes. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that apolipoprotein E (APOE) genotype may influence Parkinson's disease (PD) course, although clinical and neurochemical correlates have not been completely established. This study aimed to determine the associations of APOE genotypes (ε4 vs. non-ε4) with cerebrospinal fluid (CSF) neurodegeneration biomarkers and clinical parameters in early-stage PD patients. One hundred and seventy-five PD patients and 89 non-neurodegenerative controls grouped in APOE- ε4 carriers (28 PD; 12 controls) and non- APOE -ε4 carriers (147 PD; 78 controls) were enrolled. CSF levels of amyloid-β-42, amyloid-β-40, total and 181-phosphorylated tau, and clinical scores were compared among groups adjusting for main covariates. APOE genotypes prevalence was similar in PD and controls. PD APOE -ε4 carriers had lower amyloid-β-42 CSF levels than PD non- APOE -ε4 carriers and controls, independently from age. PD APOE -ε4 carriers also had higher total and "item 5" (attention and memory) non-motor symptoms scale scores than PD non- APOE -ε4 carriers, independently from confounding factors. APOE -ε4 genotype might thus account for a more vulnerable PD subtype characterized by prominent amyloidopathy and a greater burden of non-motor symptoms in the early disease stages. Data are available upon reasonable request. [ABSTRACT FROM AUTHOR]

We investigated how resting electroencephalography (EEG) measures are associated with risk factors for late-life cognitive impairment and dementia, including age, apolipoprotein E ɛ4 (APOE-ɛ4) carriage, and cardiometabolic burden. Resting EEG was recorded from 86 adults (50–80 years of age). Participants additionally completed the Addenbrooke's Cognitive Examination (ACE) III and had blood drawn to assess APOE-ɛ4 carriage status and cardiometabolic burden. EEG power spectra were decomposed into sources of periodic and aperiodic activity to derive measures of aperiodic component slope and alpha (7–14 Hz) and beta (15–30 Hz) peak power and peak frequency. Alpha and beta peak power measures were corrected for aperiodic activity. The aperiodic component slope was correlated with ACE-III scores but not age. Alpha peak frequency decreased with age. Individuals with higher cardiometabolic burden had lower alpha peak frequencies and lower beta peak power. APOE-ɛ4 carriers had lower beta peak frequencies. Our findings suggest that the slope of the aperiodic component of resting EEG power spectra is more closely associated with measures of cognitive performance rather than chronological age in older adults. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia, generally affecting elderly people in the age group of above 60–65 years. Amyloid deposition has been found to be a possible cause and a characteristic feature of Alzheimer's disease. Mutations, variant genotypes, or downregulation that reduce amyloid clearance or accelerate amyloid accumulation can lead to Alzheimer's disease. This study involved clinically confirmed AD patients, age matched controls of similar ethnicity, and patients who had no history of cancer or any other chronic disease. DNA and RNA extractions of samples were done as per Saguna et al. [45] and TRIzol method, respectively. Frequencies of variant genotypes were observed using the RFLP technique, whereas, for expression analysis, qPCR was performed. The association between diet, smoking status, family history, and co-morbidities was calculated using statistical tools. Expression analysis showed downregulation in more than 65% of AD cases. Hypertension and diabetes also had a significant association with AD. Allelic isoforms ε2:ε2 and ε2:ε3 tend to be less frequent among AD cases compared to controls (2.85% vs 26.15% and 11.42% vs 21.43%, respectively). Among individuals (AD cases) with ε2:ε3 and ε2:ε4, 37.5% of the patients were having severe dementia and 62.5% were having mild to moderate dementia, whereas, among individuals with ε3:ε4 and ε4:ε4, 57% were having severe dementia and 43% were having mild to moderate dementia. Besides this, all early-onset Alzheimer's patients were found to have at least one ε4 allele. The percentage of individuals with family history (cases vs controls) was 34.17% vs 3.75%, without family history 64.55% vs 95%. On comparing AD cases against controls for smoking status, the results observed are the following: chain smokers, 12.65% vs 18.75%; moderate smokers, 16.45% vs 6.25%; ex-smokers, 36.70% vs 22.50%; non-smokers, 34.17% vs 52.50%. On comparing dietary habits in AD cases against controls, the results were as follows: individuals with generally fatty diet 26.58% vs 11.25%, with mixed diet 36.70% vs 78.75%, with generally vegetarian diet 34.17% vs 10.00%, data not available 2.53% among AD cases. Family history, dietary habits, genetics, and socioeconomic status are strongly associated with the development of Alzheimer disease. Although family history or genetic makeup cannot be changed, eating habits can be changed quite easily. We simply need to go from a high-fat diet to one that is lower in fat. Regarding socioeconomic status, which includes stress of both kinds, including economic stress, stress brought on by the loss of loved ones through death or separation, and co-morbidities (hypertension and diabetes), all are manageable and even modifiable through counseling, positive behavior, and physical activity like exercise, walking, cycling, and playing games. [ABSTRACT FROM AUTHOR]

Aims: Vascular calcification (VC) and osteoporosis were previously considered two distinct diseases. However, current understanding indicates that they share common pathogenetic mechanisms. The available medicines for treating VC and osteoporosis are limited. We previously demonstrated that kefir peptides (KPs) alleviated atherosclerosis in high-fat diet (HFD)-induced apolipoprotein E knockout (ApoE−/−) mice. The present study further addressed the preventive effects of KPs on VC and osteoporosis in ApoE−/− mice fed a high-cholesterol atherogenic diet (AD).Main methods: Seven-week-old ApoE−/− and wild-type C57BL/6 mice were randomly divided into five groups (n = 6). The development of VC and osteoporosis was evaluated after AD feeding for 13 weeks in KP-treated ApoE−/− mice and compared to C57BL/6 and ApoE−/− mice fed a standard chow diet (CD).Key findings: The results indicated that KP-treated ApoE−/− mice exhibited lower serum total cholesterol, oxidized low-density lipoprotein (ox-LDL), malondialdehyde (MDA) levels, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine kinase (CK) activities, which suggested that KPs prevented hyperlipidemia and possible damages to the liver and muscle in ApoE−/− mice. KPs reduced serum tumor necrosis factor-α (TNF-α) and the local expression of TNF-α, IL-1β, and macrophage-specific CD68 markers in aortic tissues, which suggested that KPs inhibited inflammatory responses in AD-fed ApoE−/− mice. KPs reduced the deposition of lipid, collagen, and calcium minerals in the aortic roots of AD-fed ApoE−/− mice, which suggested that KPs inhibited the calcific progression of atherosclerotic plaques. KPs exerted osteoprotective effects in AD-fed ApoE−/− mice, which was evidenced by lower levels of the bone resorption marker CTX-1 and higher levels of the bone formation marker P1NP. KPs improved cortical bone mineral density and bone volume and reduced trabecular bone loss in femurs.Significance: The present data suggested that KPs attenuated VC and osteoporosis by reducing oxidative stress and inflammatory responses in AD-fed ApoE−/− mice. Our findings contribute to the application of KPs as preventive medicines for the treatment of hyperlipidemia-induced vascular and bone degeneration.

Background and objectives: Among individuals with Alzheimer's disease (AD), APOE e4 carriers with increased white matter hyperintensities (WMHs) may selectively be at increased risk of cognitive impairment. Given that the cholinergic system plays a crucial role in cognitive impairment, this study aimed to identify how APOE status modulates the associations between dementia severity and white matter hyperintensities in cholinergic pathways. Methods: From 2018 to 2022, we recruited participants (APOE e4 carriers, n = 49; non-carriers, n = 117) from the memory clinic of Cardinal Tien Hospital, Taipei, Taiwan. Participants underwent brain MRI, neuropsychological testing, and APOE genotyping. In this study, we applied the visual rating scale of the Cholinergic Pathways Hyperintensities Scale (CHIPS) to evaluate WMHs in cholinergic pathways compared with the Fazekas scale. Multiple regression was used to assess the influence of CHIPS score and APOE carrier status on dementia severity based on Clinical Dementia Rating--Sum of Boxes (CDR-SB). Results: After adjusting for age, education and sex, higher CHIPS scores tended to be associated with higher CDR-SB in APOE e4 carriers but not in the non-carrier group. Conclusions: Carriers and non-carriers present distinct associations between dementia severity and WMHs in cholinergic pathways. In APOE e4 carriers, increased white matter in cholinergic pathways are associated with greater dementia severity. In non-carriers, WMHs exhibit less predictive roles for clinical dementia severity. WMHs on the cholinergic pathway may have a different impact on APOE e4 carriers vs. non-carriers. [ABSTRACT FROM AUTHOR]

Background healthy dietary patterns have been associated with lower risk for age-related cognitive decline. However, little is known about the specific role of dietary fibre on cognitive decline in older adults. Objective this study aimed to examine the association between dietary fibre and cognitive decline in older adults and to assess the influence of genetic, lifestyle and clinical characteristics in this association. Design and participants the Invecchiare in Chianti, aging in the Chianti area study is a cohort study of community-dwelling older adults from Italy. Cognitive function, dietary and clinical data were collected at baseline and years 3, 6, 9 and 15. Our study comprised 848 participants aged ≥ 65 years (56% female) with 2,038 observations. Main outcome and measures cognitive decline was defined as a decrease ≥3 units in the Mini-Mental State Examination score during consecutive visits. Hazard ratios for cognitive decline were estimated using time-dependent Cox regression models. Results energy-adjusted fibre intake was not associated with cognitive decline during the 15-years follow-up (P  > 0.05). However, fibre intake showed a significant interaction with Apolipoprotein E (APOE) haplotype for cognitive decline (P  = 0.02). In participants with APOE-ɛ4 haplotype, an increase in 5 g/d of fibre intake was significantly associated with a 30% lower risk for cognitive decline. No association was observed in participants with APOE-ɛ2 and APOE-ɛ3 haplotypes. Conclusions and relevance dietary fibre intake was not associated with cognitive decline amongst older adults for 15 years of follow-up. Nonetheless, older subjects with APOE-ɛ4 haplotype may benefit from higher fibre intakes based on the reduced risk for cognitive decline in this high-risk group. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the main cause of cardiovascular diseases, and healthy dietary habits are a feasible strategy to prevent atherosclerosis development. Camellia oil, an edible plant oil, exhibits multiple beneficial cardiovascular effects. Our previous study showed that oral administration of camellia oil attenuated hyperglycemia, fat deposits in the liver, and the atherosclerosis index in high-fat diet (HFD)-induced obese mice. Here, an atherosclerosis model of apolipoprotein E (ApoE)-/- mice induced by HFD was used to study the effect of camellia oil on atherosclerosis, and 16S rRNA gene sequencing was used to analyze the changes in gut microbiota composition. The results showed that camellia oil significantly inhibited the formation of atherosclerotic plaques in ApoE-/- mice, which were characterized by significantly reduced levels of serum total cholesterol and enhanced levels of serum high-density lipoprotein cholesterol. The aortic levels of interleukin-6 and tumor necrosis factor were decreased. The results of the 16S rRNA analysis showed that after camellia oil interventions, the intestinal flora of ApoE-/- mice changed significantly, with the diversity of intestinal flora especially increasing, the relative abundances of Bacteroides, Faecalibaculum, Bilophila, and Leuconostoc increasing, and the Firmicutes/Bacteroidetes ratio and Firmicutes abundance decreasing. Collectively, our findings confirmed the promising value of camellia oil in preventing the development of atherosclerosis in ApoE-/- mice. Mechanistically, this preventive effect of camellia oil was probably due to its lipid-lowering activity, anti-inflammatory effects, and alteration of the gut microbiota composition in the mice. [ABSTRACT FROM AUTHOR]

Cancer-related cognitive impairment (CRCI) is a highly prevalent and debilitating symptom reported by breast cancer survivors (BCS). The etiology of CRCI remains unclear, leading to poor symptom management. Building from prior studies, BCS with the C/C genotype of apolipoprotein E (APOE) rs7412 and the T/T genotype of brain-derived neurotrophic factor (BDNF) rs6265 were hypothesized to experience more severe CRCI. Therefore, we investigated the relationships between the severity of CRCI and polymorphisms of APOE and BDNF among BCS. This was a subanalysis of data from a larger descriptive, correlational, and cross-sectional study. Subjective and objective CRCI were measured using the Patient-Reported Outcomes Measurement Information System and CANTAB Cambridge Cognitive assessment, respectively. Buccal swab samples were collected to evaluate the single nucleotide polymorphisms. Multivariable generalized linear regression models were used to analyze data. APOE rs7412 and BDNF rs6265 were significantly associated with lower self-reported cognitive abilities in a total of 353 BCS. Age was positively associated with self-reported cognitive scores, indicating that younger BCS perceived lower cognitive abilities. Individuals carrying genotype of C/T for APOE with the C/C or C/T for BDNF showed positive associations with cognitive abilities. Younger BCS with the C/C genotype for APOE rs7412 and the T/T genotype for BDNF rs6265 may be at risk for CRCI. Knowledge regarding predictive markers for CRCI symptoms is essential for precision symptom management. Further investigation with a longitudinal and translational design is necessary to explore the etiologies for CRCI. Integrating genetic phenotyping into routine clinical practice will provide nurses with unique opportunities to understand individual susceptibilities, and how symptoms may trigger other symptoms. Further, findings from these innovative investigations will provide symptom interventionists and implementation scientists with critical data to optimize individualized strategies for symptom prevention, detection, and management. [ABSTRACT FROM AUTHOR]

• A significantly higher frequency of ApoE2/E3 genotype and ApoE2 allele was observed in POMS patients compared to HCs. • Significantly lower frequencies of the ApoE3/E3 genotype and the ApoE3 allele were observed in POMS patients compared to HCs. • The ApoE2 allele may represent a novel risk factor for POMS development. Apolipoprotein E (ApoE) plays a major role in lipid homeostasis and myelination in the central nervous system. Although ApoE gene variants have been linked with cognitive impairment in the setting of Multiple sclerosis (MS), no association with disease susceptibility was found, while similar studies in pediatric-onset MS (POMS) are limited. This study aims to explore the role of ApoE gene variants in the POMS susceptibility of a Hellenic cohort and any association with disease features. 112 POMS, fulfilling the revised IPMSSG 2013 criteria, 391 adult-onset MS (AOMS) and 200 healthy controls (HCs), were enrolled. After DNA extraction, ApoE genotyping was performed by a polymerase chain reaction and sequence-specific-oligonucleotide technique. ApoE2/E3 genotype and ApoE2 allele were found to be significantly more frequent among POMS patients compared to HCs [(20.5% vs 11 %, OR [95 %]: 2.1 (1.1–4.0), p = 0.03)], and [(11% vs 5.3 %, OR [95 %]: 2.3 (1.2–4.1), p = 0.01)], respectively. Additionally, significantly lower frequencies of the ApoE3/E3 genotype and the ApoE3 allele were observed in POMS patients compared to HCs (59.8% vs 79 %, OR [95 %]:0.40 (0.24–0.65), p = 0.0005 and 79% vs 89 % 0.46, OR [95 %]: (0.30–0.73), p = 0.001)], respectively. The ApoE2 allele may represent a novel risk factor for POMS development. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. Methods We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. Results Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

Introduction: Dementia is associated with many comorbidities while being related to Apolipoprotein E (ApoE) polymorphism. However, it is unclear how these clinical illnesses and genetic factors modify the dementia risk. Methods: We enrolled 600 dementia cases and 6000 matched non-dementia controls, with identified ApoE genotype (ε4/ε4, ε4/ε3, and ε3/ε3). Eight comorbidities were selected by medical records, and counted if occurring within 3 years of enrollment. Results: The dementia group had a higher ratio of carrying +4 allele and prevalence of comorbidities than the non-dementia group. Homozygous +4 carriers presented the broken line of dementia risk with the peak age at 65--75 years and odds ratio (OR) up to 6.6. The risk only emerged after 65 years of age in +3/+4 subjects with OR around 1.6--2.4 when aged > 75 years. Cerebrovascular accident (CVA) is the commonest comorbidity (14.6%). CVA, sleep disorder, and functional gastrointestinal disorders remained as significant risk comorbidities for dementia throughout all age groups (OR = 1.7--5.0). When functional gastrointestinal disorder and +4 allele both occurred, the dementia risk exceeded the summation of individual risks OR = 3.7 and 1.9 individually, OR = 6.0 for the combination). Comorbidities could also be predictors of dementia. Conclusion: Combining the genetic and clinical information, we detected cognitive decline and optimize interventions early when the patients present a specific illness in a particular age and carry a specific ApoE allele. Of comorbidities, functional gastrointestinal disorder is the strongest predicting factor for dementia in +4 allele carriers. [ABSTRACT FROM AUTHOR]

Aims: To design a model to predict the early prognosis of patients with traumatic brain injury (TBI) based on parameters that can be quickly obtained in emergency conditions from medical history, physical examination, and supplementary examinations. Methods: The medical records of TBI patients who were hospitalized in two medical institutions between June 2015 and June 2021 were collected and analyzed. Patients were divided into the training set, validation set, and testing set. The possible predictive indicators were screened after analyzing the data of patients in the training set. Then prediction models were found based on the possible predictive indicators in the training set. Data of patients in the validation set and the testing set was provided to validate the predictive values of the models. Results: Age, Glasgow coma scale score, Apolipoprotein E genotype, damage area, serum C‐reactive protein, and interleukin‐8 (IL‐8) levels, and Marshall computed tomography score were found associated with early prognosis of TBI patients. The accuracy of the early prognosis prediction model (EPPM) was 80%, and the sensitivity and specificity of the EPPM were 78.8% and 80.8% in the training set. The accuracy of the EPPM was 79%, and the sensitivity and specificity of the EPPM were 66.7% and 86.2% in the validation set. The accuracy of the early EPPM was 69.1%, and the sensitivity and specificity of the EPPM were 67.9% and 77.8% in the testing set. Conclusion: Prediction models integrating general information, clinical manifestations, and auxiliary examination results may provide a reliable and rapid method to evaluate and predict the early prognosis of TBI patients. [ABSTRACT FROM AUTHOR]

Lipid-rich deposits called drusen accumulate under the retinal pigment epithelium (RPE) in the eyes of patients with age-related macular degeneration and Sorsby's fundus dystrophy (SFD). Drusen may contribute to photoreceptor degeneration in these blinding diseases. Stimulating β-oxidation of fatty acids could decrease the availability of lipid with which RPE cells generate drusen. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate β-oxidation and diminish lipid accumulation in fatty liver disease. In this report, we test the hypothesis that an ACC inhibitor, Firsocostat, can diminish lipid deposition by RPE cells. We probed metabolism and cellular function in mouse RPE-choroid tissue and human RPE cells. We used 13 C 6 -glucose, 13 C 16 -palmitate, and gas chromatography-linked mass spectrometry to monitor effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism. We quantified lipid abundance, apolipoprotein E levels, and vascular endothelial growth factor release using liquid chromatography-mass spectrometry, ELISAs, and immunostaining. RPE barrier function was assessed by trans-epithelial electrical resistance (TEER). Firsocostat-mediated ACC inhibition increases β-oxidation, decreases intracellular lipid levels, diminishes lipoprotein release, and increases TEER. When human serum or outer segments are used to stimulate lipoprotein release, fewer lipoproteins are released in the presence of Firsocostat. In a culture model of SFD, Firsocostat stimulates fatty acid oxidation, increases TEER, and decreases apolipoprotein E release. We conclude that Firsocostat remodels RPE metabolism and can limit lipid deposition. This suggests that ACC inhibition could be an effective strategy for diminishing pathologic drusen in the eyes of patients with age-related macular degeneration or SFD., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer’s disease (AD), the most common type of dementia in the elderly, is a chronic and progressive neurodegenerative disorder with no effective disease-modifying treatments to date. Studies have shown that an imbalance in brain metal ions, such as zinc, copper, and iron, is closely related to the onset and progression of AD. Many efforts have been made to understand metal-related mechanisms and therapeutic strategies for AD. Emerging evidence suggests that interactions of brain metal ions and apolipoprotein E (ApoE), which is the strongest genetic risk factor for late-onset AD, may be one of the mechanisms for neurodegeneration. Here, we summarize the key points regarding how metal ions and ApoE contribute to the pathogenesis of AD. We further describe the interactions between metal ions and ApoE in the brain and propose that their interactions play an important role in neuropathological alterations and cognitive decline in AD.

Dementia is a global public health concern. This study focuses on the genetic factors underlying dementia. We analyzed electronic medical records (EMR) from Taichung Veterans General Hospital, Taiwan, to confirm differences between dementia and non-dementia patients. This work was supported by Taipei Medical University [TMU111-AE1-B45]. [ABSTRACT FROM AUTHOR]

A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer's disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. Results To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. Conclusions In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.

Vascular smooth muscle cells (VSMCs) can switch from their contractile state to a synthetic phenotype resulting in high migratory and proliferative capacity and driving atherosclerotic lesion formation. The cysteine-rich LIM-only protein 4 (CRP4) reportedly modulates VSM-like transcriptional signatures, which are perturbed in VSMCs undergoing phenotypic switching. Thus, we hypothesized that CRP4 contributes to adverse VSMC behaviours and thereby to atherogenesis in vivo. The atherogenic properties of CRP4 were investigated in plaque-prone apolipoprotein E (ApoE) and CRP4 double-knockout (dKO) as well as ApoE-deficient CRP4 wildtype mice. dKO mice exhibited lower plaque numbers and lesion areas as well as a reduced content of α-smooth muscle actin positive cells in the lesion area, while lesion-associated cell proliferation was elevated in vessels lacking CRP4. Reduced plaque volumes in dKO correlated with significantly less intra-plaque oxidized low-density lipoprotein (oxLDL), presumably due to upregulation of the antioxidant factor peroxiredoxin-4 (PRDX4). This study identifies CRP4 as a novel pro-atherogenic factor that facilitates plaque oxLDL deposition and identifies the invasion of atherosclerotic lesions by VSMCs as important determinants of plaque vulnerability. Thus, targeting of VSMC CRP4 should be considered in plaque-stabilizing pharmacological strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] • The regional cerebral oxygen saturation (rScO 2) and quantitative electroencephalogram (QEEG) were significantly changed at the early stage of TBI patients. • The APOE ε4 allele may lead to deterioration of rScO 2 and QEEG at the early stage of TBI patients. • The relationships between APOE gene polymorphism and rScO 2 and QEEG at an early stage of TBI are important and worth further studying. To investigate the influence of apolipoprotein E (APOE) gene polymorphism on regional cerebral oxygen saturation (rScO 2) and quantitative electroencephalogram (QEEG) at the early phase of adult traumatic brain injury (TBI). clinical data of TBI patients who were admitted to the neurosurgery intensive care unit (NICU) were retrospectively evaluated and studied, and data of healthy volunteers were recruited as control. The APOE genotypes were genotyped by quantitative fluorescent polymerase chain reaction (QF-PCR). The rScO 2 and brain electrical activity of all the participants involved in this research were measured by near-infrared spectroscopy (NIRS) and QEEG respectively. The average rScO 2 of TBI patients was significantly lower than that of the normal controls (P < 0.0001). And the EEG of the TBI patients has showed more irregular slow-wave activities than that of the normal controls. Furthermore, the above changes were more significant in the APOE ε4 carriers in the early stage of TBI patients. The APOE ε4 allele may be associated with poor rScO 2 and more slow-wave activities at the early stage of TBI. To clarify the effect of APOE gene polymorphism on the condition of patients with TBI may be helpful for the design and management of individualized treatment programs. [ABSTRACT FROM AUTHOR]

The role of iron in atherosclerosis is still a controversial and unsolved issue. Here, we investigated serum iron, expression of iron regulatory, transport and storage proteins, pro-inflammatory chemokines and cytokines in ApoE–/– mice. We demonstrated that ApoE–/– induced atherosclerosis and an increase in iron contents, expression of transferrin receptor 1 (TfR1), iron regulatory proteins (IRPs), heme oxygenase 1 (HO1), cellular adhesion molecules and pro-inflammatory cytokines, production of reactive oxygen species (ROS), and a reduction in expression of superoxide dismutase and glutathione peroxidase enzyme in aortic tissues. All of these changes induced by ApoE deficiency could be significantly abolished by deferoxamine. The data showed that the increased iron in aortic tissues was mainly due to the increased iron uptake via IRP/TfR1 upregulation. These findings plus a brief analysis of the controversial results reported previously showed that ApoE deficiency-induced atherosclerosis is partly mediated by the increased iron in aortic tissues.

• Single cell based analyses promote greater understanding of Alzheimer's disease. • Mitochondrial function and energy production are implicated in a mouse model. • Mouse Apoe is involved in the generation of specific polyadenylated transcripts. • Single cell studies could inform treatments that target specific brain cell types. A dataset of single-nucleus RNA sequencing (snRNAseq) data was analyzed using Seurat, Sierra, and Ingenuity Pathway Analysis (IPA) programs to assess differentially expressed genes (DEGs) and differential transcript usage (DTU) in mouse hippocampal cell types. Seurat identified DEGs between the wild type (WT) and Apoe knockout (EKO) mice. IPA identified 11 statistically significant canonical pathways in >1 cell type. Sierra identified Sipa1l1 with DTU between WT and EKO samples. Analysis of the Sipa1l1 peak region identified an alternative non-canonical polyadenylation signal and a putative cytoplasmic polyadenylation element. APOE regulation of gene transcription and co-transcriptional RNA processing may underlie Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. Methods: We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. Results: Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. Conclusions: We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4. [ABSTRACT FROM AUTHOR]

Introduction: Human study shows that elevated C-reactive protein (CRP) in blood impacts apolipoprotein E (APOE) ε4, but not APOE ε3 or APOE ε2, genotype to increase the risk of Alzheimer's disease (AD). However, whether CRP is directly involved in cellular AD pathogenesis and in which type of neuronal cells of APOE ε4 carriers are unknown. Methods: We aimed to use different primary neuronal cells and investigate if CRP induces cellular AD pathology depending on APOE genotypes. Here the different primary neuronal cells from the different APOE genotype knock-in mice cortex were isolated and used. Results: Monomeric CRP (mCRP) increased amyloid beta production and, in parallel, induced tau phosphorylation in addition to their related proteins in the primary neurons in a pattern of APOE ε4 > APOE ε3 > APOE ε2 in a dose- and time-dependent manner. Consistently, mCRP induced the staining of other neurodegenerative biomarkers, including Fluoro-Jade B stain (FjB), TUNEL and Cleaved Caspase-3, in primary neurons in a similar pattern of APOE ε4 > APOE ε3 > APOE ε2. In contrast, pentameric CRP (pCRP) had a tendency to induce cellular ADpathology but did not reach statistical significance. On the other hand, it is intriguing that regardless of APOE genotype, mCRP did not influence the expressions of Iba-1 and CD68 in primarymicroglia or the expression of glial fibrillary acidic protein in primary astrocytes, and additionally mCRP did not affect the secretions of interleukin (IL)-1α, IL-1β, and tumor necrosis factor α from these cells. Discussion: This is the first report to demonstrate that mCRP directly induces cellular AD pathogenesis in neurons in an APOE genotype-dependent pattern, suggesting that mCRPplays a role as amediator involved in the APOE ε4-related pathway forADduring chronic inflammation. [ABSTRACT FROM AUTHOR]

To investigate the correlation between ApoE gene polymorphism and the risk of lower extremity arterial disease (LEAD) in T2DM patients of Han nationality in northern China. One hundred and fifty patients with T2DM and 150 patients with T2DM combined with LEAD were enrolled in the study and assigned to the control group and the case group, respectively. The results revealed that the number of epsilon 2 (ε2) genotype carriers in the case group was significantly lower than that in the control group (case vs control: 8.0% vs 15.4%), and the distribution of the ε2 allele frequency was similar to that of the genotype (case vs control: 4.0% vs 8.4%). A binary logistic regression analysis revealed that age, waist-to-hip ratio (WHR), and gender were risk factors for T2DM with LEAD and that the ApoE ε2 carriers was a protective factor (odds ratio [OR] 0.380; 95% confidence interval [CI] 0.162-0.892; P =.026). In male subjects, ε2 carriers were more common in the control group (case vs control:7.8% vs 24.1%), while epsilon 4 (ε4) carriers were more common in the case group (case vs control: 23.3% vs 8.6%); the distribution of frequency of ε2 and ε4 alleles was more common in the control group and the case group, respectively (case vs control: 3.9% vs 12.1%, 12.8% vs 5.2%). In male, age and WHR were risk factors for the disease, and being an ε2 carrier was a protective factor. Being an ApoE gene ε2 carrier is a protective factor for LEAD in male patients with T2DM that are of Han nationality in northern China. [ABSTRACT FROM AUTHOR]

The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer’'s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and Aβ peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the Aβ17–24 region of Aβ and promoted Aβ fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in Aβ pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and Aβ and ultimately the slower rate of brain Aβ deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.

Dementia is a global public health concern. This study focuses on the genetic factors underlying dementia. We analyzed electronic medical records (EMR) from Taichung Veterans General Hospital, Taiwan, to confirm differences between dementia and non-dementia patients. This work was supported by Taipei Medical University [TMU111-AE1-B45].

Human apolipoprotein E (ApoE) was first identified as a polymorphic gene in the 1970s; however, the genetic association of ApoE genotypes with late-onset sporadic Alzheimer's disease (sAD) was only discovered 20 years later. Since then, intensive research has been undertaken to understand the molecular effects of ApoE in the development of sAD. Despite three decades' worth of effort and over 10,000 papers published, the greatest mystery in the ApoE field remains: human ApoE isoforms differ by only one or two amino acid residues; what is responsible for their significantly distinct roles in the etiology of sAD, with ApoE4 conferring the greatest genetic risk for sAD whereas ApoE2 providing exceptional neuroprotection against sAD. Emerging research starts to point to a novel and compelling hypothesis that the sialoglycans posttranslationally appended to human ApoE may serve as a critical structural modifier that alters the biology of ApoE, leading to the opposing impacts of ApoE isoforms on sAD and likely in the peripheral systems as well. ApoE has been shown to be posttranslationally glycosylated in a species-, tissue-, and cell-specific manner. Human ApoE, particularly in brain tissue and cerebrospinal fluid (CSF), is highly glycosylated, and the glycan chains are exclusively attached via an O -linkage to serine or threonine residues. Moreover, studies have indicated that human ApoE glycans undergo sialic acid modification or sialylation, a structural alteration found to be more prominent in ApoE derived from the brain and CSF than plasma. However, whether the sialylation modification of human ApoE has a biological role is largely unexplored. Our group recently first reported that the three major isoforms of human ApoE in the brain undergo varying degrees of sialylation, with ApoE2 exhibiting the most abundant sialic acid modification, whereas ApoE4 is the least sialylated. Our findings further indicate that the sialic acid moiety on human ApoE glycans may serve as a critical modulator of the interaction of ApoE with amyloid β (Aβ) and downstream Aβ pathogenesis, a prominent pathologic feature in AD. In this review, we seek to provide a comprehensive summary of this exciting and rapidly evolving area of ApoE research, including the current state of knowledge and opportunities for future exploration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Moon, Luo, Chugh and Zhao.)

Alzheimer's disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 AD and 29 controls (Ctrl) were studied to balance the number of ε4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, ε4 allele carriers (APOE4+ for those carrying 1 or 2 ε4s and APOE4- for non-ε4 carriers), and differences in ε3ε3 and ε3ε4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). The region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology.

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is primarily expressed and secreted by the liver. The hormone is crucial for regulation of glucose homeostasis, lipid metabolism, and energy balance. Compared with natural FGF21, FGF21 analogs have become drug candidates for the treatment of cardiovascular and metabolic diseases owing to their long half-life and greater stability in vitro . Apolipoprotein E ( Apoe) -knockout ( Apoe -/- ) mice exhibit progressive disruptions in lipid metabolism in vivo and develop further atherosclerosis pathological features owing to Apoe deletion. Therefore, this study used an Apoe -/- mouse model to investigate the effects of a long-acting FGF21 analog (PF-05231023) on lipid metabolism and related parameters. Eighteen Apoe -/- female mice were fed a Western diet equivalent for 12 weeks, and then randomly assigned to intraperitoneally receive either physiological saline (the control group) or 10 mg/kg PF-05231023 (the treatment group) three times a week for seven consecutive weeks. Body composition, glucose tolerance, blood and liver cholesterol, triglyceride levels, liver vacuolization levels, peri-ovarian white adipocyte hypertrophy, aortic atherosclerotic plaque formation, and the expression of genes related to lipid metabolism in adipose tissue were subsequently assessed before and after treatment. The aortic atherosclerotic plaque area was reduced in mice in the PF-05231023 treatment group compared with that in the saline group. Although the effect of PF-05231023 on the plasma biochemical indexes of mice was small, it significantly reduced lipid levels and lipid droplet accumulation in the liver, and reduced adipocyte hypertrophy in white adipose tissue. Transcriptome analysis of adipose tissue showed that PF-05231023 treatment downregulated the expression of lipid synthesis-related genes and inhibited the sterol regulatory element binding transcription factor 1 gene, thereby improving lipid deposition. PF-05231023 effectively improved the lipid metabolism of Apoe -/- mice, demonstrating an anti-atherosclerotic effect and providing a scientific basis and experimental foundation for the clinical treatment of cardiovascular diseases by using long-acting FGF21 analogs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Liu, Yue, Zhang, Li and Wei.)

Background: This study examines the association between apolipoprotein E (APOE) genotypes and metabolic syndrome (MetS) in an older urban population in South India, as part of the Tata Longitudinal Study on Aging., Methods: A total of 618 participants aged 45 and above were analyzed cross-sectionally for the association between APOE carrier status and MetS (based on both NCEP ATP III and Consensus criteria)., Results: Despite the high prevalence of MetS observed in this cohort (51.62 % by NCEP-ATP III and 61.33 % by Consensus criteria), multivariable logistic regression revealed no significant association between APOE genotypes and MetS under both criteria. However, specific associations were noted in age and sex-stratified analyses; notably, E2 carriers under 60 showed 0.42-fold decreased odds (95%CI:0.20,0.89, p-value-0.023) for an increased waist circumference, and E4 carriers above 60 were at 1.85 times increased odds (95 % CI:1.04,3.28, p-value<0.05) for decreased HDL., Conclusion: These findings suggest that while APOE genotypes influence certain metabolic parameters, their impact on MetS may be limited in this urban setting, possibly overshadowed by environmental factors and lifestyle influences, which was highlighted by the differences seen in its sister rural cohort., Competing Interests: All authors declare no conflicts of interest., (© 2024 The Authors. Published by Elsevier Inc.)