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Lipids participate in amyloid precursor protein (APP) trafficking and processing ‒ important factors in the initiation of Alzheimer's disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signal...
Citations
... Lipids have been reported to be involved in the transport and processing of β-amyloid precursor protein (APP) and to influence the synthesis of β-amyloid (Penke et al. 2018). β-Amyloid is a neurotoxic one-way transmembrane protein, and its aberrant accumulation in the brain is considered to be a key factor in the development of AD (O'Brien and Wong 2011). ...
Objective
This study aimed to explore the causal effects of lipidome on Alzheimer's disease (AD) and the mediated effects of the metabolites using Mendelian randomization (MR).
Methods
Data were obtained in genome‐wide association studies, and single‐nucleotide polymorphisms were screened according to the underlying assumptions of MR. Subsequently, weighted inverse variance was used to analyze the causality of lipidome with AD as well as the mediated effects of metabolites. Finally, MR‐Egger, Cochran's Q, and sensitivity analysis were used to assess horizontal pleiotropy, heterogeneity, and robustness of the results, respectively.
Results
The MR analysis showed that phosphatidylcholine (PC) (15:0_18:2) (mediated proportion: 18.30%, p = 0.024) and phosphatidylethanolamine (PE) (18:0_18:2) (mediated proportion: 14.60%, p = 0.028) mediated the reduction of AD risk by lowering betaine levels, which revealed lipidomic susceptibility. The MR‐Egger intercept showed no horizontal pleiotropy for all results (p ≥ 0.05). Cochran's Q showed heterogeneity in some of the results. Sensitivity analysis indicated that all results were robust.
Conclusion
Our findings reveal the pathways through which PC (15:0_18:2) and PE (18:0_18:2) mediated the reduction of AD risk by lowering betaine levels.
... However, whether Hsp72 upregulation is beneficial or detrimental for the occurrence of POMC neurodegeneration was not determined in that study. As discussed later, 4-HNE results in carbonylationinduced cleavage of Hsp70.1 (Figure 4g) [5,8,48], and at the same time, 4-HNE also induces Hsp70.1 upregulation through the nuclear export of Daxx (death association protein 6) ( Figure 4h) [75]. HNE-induced translocation of Daxx from the nucleus to the cytoplasm releases heat shock transcription factor 1 (HSF1) and allows it bind to its DNA recognition elements to increase Hsp70.1 expression [76]. ...
Excessive consumption of vegetable oils such as soybean and canolla oils containing ω-6 polyunsaturated fatty acids is considered one of the most important epidemiological factors leading to the progression of lifestyle-related diseases. However, the underlying mechanism of vegetable-oil-induced organ damage is incompletely elucidated. Since proopiomelanocortin (POMC) neurons in the hypothalamus are related to the control of appetite and energy expenditure, their cell degeneration/death is crucial for the occurrence of obesity. In patients with metabolic syndrome, saturated fatty acids, especially palmitate, are used as an energy source. Since abundant reactive oxygen species are produced during β-oxidation of the palmitate in mitochondria, an increased amount of 4-hydroxy-2-nonenal (4-HNE) is endogenously generated from linoleic acids constituting cardiolipin of the inner membranes. Further, due to the daily intake of deep-fried foods and/or high-fat diets cooked using vegetable oils, exogenous 4-HNE being generated via lipid peroxidation during heating is incorporated into the blood. By binding with atheromatous and/or senile plaques, 4-HNE inactivates proteins via forming hybrid covalent chemical addition compounds and causes cellular dysfunction and tissue damage by the specific oxidation carbonylation. 4-HNE overstimulates G-protein-coupled receptors to induce abnormal Ca²⁺ mobilization and µ-calpain activation. This endogenous and exogenous 4-HNE synergically causes POMC neuronal degeneration/death and obesity. Then, the resultant metabolic disorder facilitates degeneration/death of hippocampal neurons, pancreatic β-cells, and hepatocytes. Hsp70.1 is a molecular chaperone which is crucial for both protein quality control and the stabilization of lysosomal limiting membranes. Focusing on the monkey hippocampus after ischemia, previously we formulated the ‘calpain–cathepsin hypothesis’, i.e., that calpain-mediated cleavage of carbonylated Hsp70.1 is a trigger of programmed neuronal death. This review aims to report that in diverse organs, lysosomal cell degeneration/death occurs via the calpain–cathepsin cascade after the consecutive injections of synthetic 4-HNE in monkeys. Presumably, 4-HNE is a root substance of lysosomal cell death for lifestyle-related diseases.
... This leads to the extracellular accumulation of Aβ peptides that then form oligomers and senile plaques. 34 In turn, this appears to elicit a tauopathy in which we see a neurotoxic cascade involving membrane damage, mitochondrial dysfunction, cytoskeletal changes, and ultimately, the hyperphosphorylation of tau, which leads to microtubule destabilization [35][36][37][38] and tau NFT. These changes appear to ultimately cause neuronal dysfunction and cellular death. ...
With increasing age comes the inevitable decline in proteostasis, where chaperone and co-chaperone activity be-comes imbalanced. These changes lead to global disturbances and pathogenic rewiring of the chaperone system intoepichaperones consisting of protein networks that are ultimately dysfunctional. Such imbalances in proteostasis mayfavor mechanisms that can lead to neurological diseases, such as Alzheimer’s disease (AD). Consequently, there hasbeen an increase in research activity toward finding small molecules that can re-balance the chaperone and co-chaperone machinery to counter the effects of disease resulting from old age. The Hsp90 co-chaperone FKBP51 hasrecently been identified as a protein whose induction not only increases with age but is elevated further in AD cells.Significantly, FKBP51 plays a role in the Hsp90-dependent isomerization of tau, which in turn influences itsphosphorylation and susceptibility to aggregation. We hypothesize that FKBP51 is a major player that is able to elicittauopathy in response to amyloid-beta senile plaques that damage the brain. We propose that elevated FKBP51 levelsresult in an abnormal FKBP51–Hsp90 activity that alters the normal processing of tau, which manifests as hyper-phosphorylation and oligomerization of tau. Thus, the Hsp90–FKBP51 complex is emerging as a drug target againstAD. In support of this idea, the structure of the FKBP51–Hsp90 complex was recently described, and significantly,the small-molecule dihydropyridine LA1011 was shown to be able to disrupt the Hsp90–FKBP51 complex. LA1011was previously shown to effectively prevent neurodegeneration in the APPxPS1 AD transgenic mouse model. Thisreview looks at the role of Hsp90 and its co-chaperones in AD with a focus on FKBP51.
... Accumulating evidence points at associations between APOE4 and dysregulated lipid homeostasis and transport (Blanchard et al., 2022;Penke et al., 2018;Tcw et al., 2022). Astrocytes are the predominant source of ApoE in the brain and play critical roles in brain lipid metabolism by secreting ApoE associated with lipids in the form of lipoprotein-like particles that transfer lipids, including fatty acids retrieved from the circulation, to neurons (Poirier et al., 1991;Sun et al., 1998). ...
APOE4 encoding apolipoprotein (Apo)E4 is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is key in intercellular lipid trafficking. Fatty acids are essential for brain integrity and cognitive performance and are implicated in neurodegeneration. We determined the sex‐ and age‐dependent effect of AD and APOE4 on brain free fatty acid (FFA) profiles. FFA profiles were determined by LC–MS/MS in hippocampus, cortex, and cerebellum of female and male, young (≤3 months) and older (>5 months), transgenic APOE3 and APOE4 mice with and without five familial AD (FAD) mutations (16 groups; n = 7–10 each). In the different brain regions, females had higher levels than males of either saturated or polyunsaturated FFAs or both. In the hippocampus of young males, but not of older males, APOE4 and FAD each induced 1.3‐fold higher levels of almost all FFAs. In young and older females, FAD and to a less extent APOE4‐induced shifts among saturated, monounsaturated, and polyunsaturated FFAs without affecting total FFA levels. In cortex and cerebellum, APOE4 and FAD had only minor effects on individual FFAs. The effects of APOE4 and FAD on FFA levels and FFA profiles in the three brain regions were strongly dependent of sex and age, particularly in the hippocampus. Here, most FFAs that are affected by FAD are similarly affected by APOE4. Since APOE4 and FAD affected hippocampal FFA profiles already at young age, these APOE4‐induced alterations may modulate the pathogenesis of AD. image
... Los cerebrósidos que contienen ácido lignocérico se denominan querasina, mientras que los que contienen ácido cerebrónico se denominan frenosina. Estos glucolípidos o glucoesfingolípidos se encuentran principalmente en el cerebro y en el tejido nervioso periférico, como aislante y capa de protección de las células nerviosas.Los gangliósidos son lípidos que cuentan con cabezas polares muy grandes formadas por unidades de oligosacáridos cargadas negativamente, y que poseen una o más unidades de ácido N-acetilneuramínico (NANA) o ácido siálico que tiene una carga negativa a pH 7. Están concentrados en gran cantidad en las células ganglionares del sistema nervioso central y del sistema nervioso periférico, especialmente en las terminaciones nerviosas(Penke et al., 2018). Los gangliósidos son los componentes principales de la membrana celular del animal y se encuentran en abundancia en la membrana plasmática de las neuronas; ...
El texto que se pone a consideración del lector, en su edición digital, revisada y corregida, ha sido preparado con fines académicos, para la formación de médicos veterinarios y/o zootecnistas, en el contexto del Altiplano de Puno-Perú; sin embargo, puede servir como referencia para todo lector interesado en la nutrición animal. Incluye seis unidades temáticas: fisiología digestiva de los animales, como uno de los procesos nutricionales clave, seguida de energía (carbohidratos), lípidos, proteínas, minerales y vitaminas, y una unidad temática adicional sobre la evaluación de la composición química y calorimetría de los alimentos.
... Consistent with our findings that the IFI30 gene is highly expressed in patients with AD, GILT is highly expressed in microglia surrounding Aβ and is involved in Aβ clearance (42,43). Abnormalities of lipid metabolism in the brain are characteristic of AD (44,45). It is possible to reduce the risk of AD by converting phosphatidylcholine to lysophosphatidylcholine-DHA in liver tissues and transporting it into the brain across the blood-brain barrier (46,47). ...
... Finally, the drugs targeting the above genes were retrieved from the DrugBank database. An excess of copper (DB09130) acts as a catalyst for a variety of biological processes (57), accumulating in neurofibrillary tangles and regulating APP gene expression (45,46). Aβ peptide interaction with copper and other metals is thought to promote gain-of-function activity and lead to neurotoxicity (15). ...
Alzheimer's disease (AD) is a chronic neurodegenerative disease, and its underlying genes and treatments are unclear. Abnormalities in copper metabolism can prevent the clearance of β-amyloid peptides and promote the progression of AD pathogenesis. Therefore, the present study used a bioinformatics approach to perform an integrated analysis of the hub gene based on cuproptosis that can influence the diagnosis and treatment of AD. The gene expression profiles were obtained from the Gene Expression Omnibus database, including non-demented (ND) and AD samples. A total of 2,977 cuproptosis genes were retrieved from published articles. The seven hub genes associated with cuproptosis and AD were obtained from the differentially expressed genes and WGCNA in brain tissue from GSE33000. The GO analysis demonstrated that these genes were involved in phosphoribosyl pyrophosphate, lipid, and glucose metabolism. By stepwise regression and logistic regression analysis, we screened four of the seven cuproptosis genes to construct a diagnostic model for AD, which was validated by GES15222, GS48350, and GSE5281. In addition, immune cell infiltration of samples was investigated for correlation with these hub genes. We identified six drugs targeting these seven cuproptosis genes in DrugBank. Hence, these cuproptosis gene signatures may be an important prognostic indicator for AD and may offer new insights into treatment options.
... A significant amount of neuronal membrane reorganization takes place as part of memory encoding and neuroplasticity, particularly in the hippocampus [42]. This process is influenced by slight variations in membrane lipid composition, and can predispose to AD pathology [43]. Cholesterol and saturated fatty acids may promote the formation of A 42 through the complementary APP intracellular domain, causing excess tau phosphorylation [44]. ...
Background
Mechanistic studies in animal models implicate a role for saturated fatty acids in neurodegeneration, but validation of this finding in human studies is still lacking.
Objective
We investigated how cerebrospinal levels of sphingomyelins (SM) and phosphatidylcholine (PC)-containing saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids associate with total tau and phosphorylated tau (p-tau).
Methods
Cerebrospinal fluid (CSF) lipids were measured in two cohorts, a discovery and a confirmation cohort of older non-demented individuals from the University of Southern California and Huntington Medical Research Institutes cohorts. Lipid analysis was performed using hydrophilic interaction liquid chromatography, and individual PC and SM lipid species were measured using tandem mass spectrometry. In addition, CSF levels of Aβ42, total tau, and p-tau-181 were measured using an MSD multiplex assay.
Results
The discovery cohort (n = 47) consisted of older individuals and more females compared to the confirmation cohort (n = 46). Notwithstanding the age and gender differences, and a higher p-tau, Aβ42, and LDL-cholesterol in the discovery cohort, CSF concentrations of dipalmitoyl-PC (PC32a:0) were significantly associated with p-tau in both cohorts. Similarly, total saturated PC but not mono or polyunsaturated PCs correlated with p-tau concentrations in both cohorts.
Conclusion
Saturated PC species in CSF associate with early markers of neurodegeneration and are potential early disease progression biomarkers. We propose mechanisms by which saturated PC may promote tau hyperphosphorylation.
... Consistent with the findings from our study, lower HDL-C levels have been previously reported to be associated with more severe white matter lesion changes, leading to AD and mild cognitive impairment; this represents a transitional stage between normal aging and AD [27]. The APOE 4 allele is the strongest known genetic risk factor for sporadic AD and is also a risk factor for LBD [28]. ...
Background
The relationship between cholesterol level and the risk of developing Alzheimer’s disease has been well established, but the relationship between cholesterol level and Lewy body dementia (LBD) is still not well known.
Objective
The aim of this case-control study was to explore the association between blood cholesterol levels and LBD in Chinese older adults.
Methods
A total of 65 patients with LBD and 110 older adult controls were enrolled during the study period. The levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting glucose were measured separately. The associations between LBD, blood cholesterol levels, and fasting glucose levels were assessed using multiple binary logistic regression analyses adjusted for multiple covariates.
Results
Increased plasma LDL-C levels and lower HDL-C levels were independently associated with the risk of LBD in models adjusted for age, sex, education, alcohol use status, smoking status, and vascular disorders. Higher fasting glucose levels may be associated with the risk of LBD.
Conclusion
The results of this study suggest that elevated levels of LDL-C and reduced levels of HDL-C were associated with LBD development and therefore are potential nutritional risk factors for LBD. Adjusting diet and individualized and effective cholesterol-lowering therapy in high-risk adults may aid in the prevention or management of LBD.
... Phospholipids are the most abundant lipids in brain membranes, and they control membrane fluidity and thickness, as well as membrane protein activity [265,266]. There are lower levels of several phospholipids in AD brains, and several studies report a decrease in PS [267], PI [268], PC, and PE [269,270], although increases in certain species have also been reported [271]. ...
Membranes are mainly composed of a lipid bilayer and proteins, constituting a checkpoint for the entry and passage of signals and other molecules. Their composition can be modulated by diet, pathophysiological processes, and nutritional/pharmaceutical interventions. In addition to their use as an energy source, lipids have important structural and functional roles, e.g., fatty acyl moieties in phospholipids have distinct impacts on human health depending on their saturation, carbon length, and isometry. These and other membrane lipids have quite specific effects on the lipid bilayer structure, which regulates the interaction with signaling proteins. Alterations to lipids have been associated with important diseases, and, consequently, normalization of these alterations or regulatory interventions that control membrane lipid composition have therapeutic potential. This approach, termed membrane lipid therapy or membrane lipid replacement, has emerged as a novel technology platform for nutraceutical interventions and drug discovery. Several clinical trials and therapeutic products have validated this technology based on the understanding of membrane structure and function. The present review analyzes the molecular basis of this innovative approach, describing how membrane lipid composition and structure affects protein-lipid interactions, cell signaling, disease, and therapy (e.g., fatigue and cardiovascular, neurodegenerative, tumor, infectious diseases).
... It is also speculated that lipid depletion in the brain associated with aging and/or disease may lead to alterations in channel function 85 . Furthermore, it has been hypothesised that variations in cholesterol content in the neuron cell membrane can indirectly modulate Ca + permeability in Alzheimer's patients 85,86 . ...
The Arabian camel (Camelus dromedarius) is the most important livestock animal in arid and semi-arid regions and provides basic necessities to millions of people. In the current context of climate change, there is renewed interest in the mechanisms that enable camelids to survive in arid conditions. Recent investigations described genomic signatures revealing evolutionary adaptations to desert environments. We now present a comprehensive catalogue of the transcriptomes and proteomes of the dromedary kidney and describe how gene expression is modulated as a consequence of chronic dehydration and acute rehydration. Our analyses suggested an enrichment of the cholesterol biosynthetic process and an overrepresentation of categories related to ion transport. Thus, we further validated differentially expressed genes with known roles in water conservation which are affected by changes in cholesterol levels. Our datasets suggest that suppression of cholesterol biosynthesis may facilitate water retention in the kidney by indirectly facilitating the AQP2-mediated water reabsorption. Fernando Alvira-Iraizoz and Benjamin T. Gillard et al. comprehensively catalogue the kidney transcriptome and proteome of dromedary camels in response to chronic dehydration stress and subsequent acute rehydration. Their results suggest that the suppression of the cholesterol biosynthesis may facilitate water retention in the dromedary camel kidney, providing further insight into how these animals survive in arid conditions.
