Brain Lipid Research Articles

Does the epigenetic expression of obesity, insulin resistance and their metabolic sequelae contribute to brain senescence?

Cognitive senescence and brain shrinkage have been reported in Alzheimer’s disease and is often associated with obesity but the pathophysiologic factors which bring about the neural declines remain unclear. A retrospective examination of factors of Insulin resistance and obesity in lean and obese rats indicated that final body weights of obese phenotype were more than double those of their lean littermates throughout adulthood, and carcass fat content at 10.5 months of age 15-fold greater than similarly fed lean littermates. In addition, the life span of the obese phenotype was decreased by approximately 30% in both male and female rats compared to their lean littermates. In addition, glycemic parameters indicated that the obese rats developed significant insulin resistance, while brain lipid, protein and DNA content were significantly reduced by one third or more in the obese phenotype by ~10 months of age, when they had approached their peak body weights. These observations suggest that the onset and progression obesity and its metabolic sequelae contributes to brain shrinkage, decreased DNA and protein content, key factors in the development of cognitive senescence in aging in this strain of rat.

The Epigenetic Expression of Obesity and Its Metabolic Sequelae Contribute to Brain Senescence and Decreased Longevity in Aging Obese LA/Ntul//-cp Rats

Cognitive senescence and brain shrinkage have been reported in Alzheimer’s disease and is often associated with obesity but the pathophysiologic factors which bring about the neural declines remain unclear. A retrospective examination of factors of Insulin resistance and obesity in lean and obese rats indicated that final body weights of obese phenotype were more than double those of their lean littermates throughout adulthood, and carcass fat content at 10.5 months of age 15-fold greater than similarly fed lean littermates. In addition, the life span of the obese phenotype was decreased by approximately 30% in both male and female rats compared to their lean littermates. In addition, glycemic parameters indicated that the obese rats developed significant insulin resistance, while brain lipid, protein and DNA content were significantly reduced by one third or more in the obese phenotype by ~10 months of age, when they had approached their peak body weights. These observations suggest that the onset and progression obesity and its metabolic sequelae contributes to brain shrinkage, decreased DNA and protein content, key factors in the development of cognitive senescence in aging in this strain of rat.

Gut content microbiota dysbiosis and dysregulated lipid metabolism in diarrhea caused by high-fat diet in a fatigued state.

Previous evidence has indicated that fatigue and a high-fat diet (HFD) cause the adaptive organism responses to be dysregulated, resulting in gastrointestinal (GI) disorders. Generally, gut microbiota plays a crucial role in GI disorders. However, the impact of fatigue and an HFD on the microbiome and GI disorders remains to be fully explored. Mice were randomly divided into the control group (CCN), standing group (CSD), lard group (CLD), and standing + lard group (CSLD). Mice in the CSD and CSLD groups stood on the multiple-platform apparatus for four h per day for 14 consecutive days. From the eighth day, mice in the CLD and CSLD groups were fed intragastric lard and the CCN and CSD groups were subjected to intragastric treatment with sterile water, 0.4 mL per each, twice a day for seven days. Subsequently, we analyzed the characteristics and interaction relationship of gut content microbiota (GCM), brain-gut peptides, and lipid metabolism. Mice in the CSLD group were in a fatigued state and had diarrhea. Compared with the CCN group, high-density lipoproteins were significantly lower, and the lipid droplet optical density value was substantially higher in the CSLD group (p < 0.05). CSLD mice presented significant structural damage to the small intestine and considerably higher β-endorphin, cholecystokinin, and somatostatin (p < 0.05). Bacillus, Gemella, and Bosea were the characteristic bacteria of the CSLD group, and Gemella was significantly negatively correlated with total cholesterol. Gut microbiota dysbiosis and dysregulated lipid metabolism contribute to diarrhea caused by an HFD diet in a fatigued state.

Anethole prevents high-calorie diet-induced brain lipid peroxidation in rats and normalizes superoxide dismutase activity

Anethole prevents high-calorie diet-induced brain lipid peroxidation in rats and normalizes superoxide dismutase activity

Lipids and Secretory Vesicle Exocytosis.

In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically. Discrete changes in phosphoinositides concentration are involved in multiple trafficking events including exocytosis and endocytosis. Lipid-modifying enzymes such as the DDHD2 isoform of phospholipase A1 were recently shown to contribute to memory acquisition via dynamic modifications of the brain lipid landscape. Considering the increasing reports on neurodegenerative disorders associated with aberrant intracellular trafficking, an improved understanding of the control of lipid pathways is physiologically and clinically significant and will afford unique insights into mechanisms and therapeutic methods for neurodegenerative diseases. Consequently, this chapter will discuss the different classes of lipids, phospholipase enzymes, the evidence linking them to synaptic neurotransmitter release and how they act to regulate key steps in the multi-step process leading to neuronal communication and memory acquisition.

Nanomedicine targeting brain lipid metabolism as a feasible approach for controlling the energy balance.

Targeting brain lipid metabolism is a promising strategy to regulate the energy balance and fight metabolic diseases such as obesity. The development of stable platforms for selective delivery of drugs, particularly to the hypothalamus, is a challenge but a possible solution for these metabolic diseases. Attenuating fatty acid oxidation in the hypothalamus via CPT1A inhibition leads to satiety, but this target is difficult to reach in vivo with the current drugs. We propose using an advanced crosslinked polymeric micelle-type nanomedicine that can stably load the CPT1A inhibitor C75-CoA for in vivo control of the energy balance. Central administration of the nanomedicine induced a rapid attenuation of food intake and body weight in mice via regulation of appetite-related neuropeptides and neuronal activation of specific hypothalamic regions driving changes in the liver and adipose tissue. This nanomedicine targeting brain lipid metabolism was successful in the modulation of food intake and peripheral metabolism in mice.

Target Organ Toxicity in Rats After Subchronic Oral Exposure to Soil Extracts Containing a Complex Mixture of Contaminants.

Complex mixtures of unknown contaminants present a challenge to identify toxicological risks without using large numbers of animals and labor-intensive screens of all organs. This study examined soil extracts from a legacy-contaminated pesticide packaging and blending site. HepG2 cytotoxicity was used as an initial screen of 18 soil samples; then, three extracts (A, B and C) from different locations at the study site were used for testing in animals. The first two extracts were identified as the most toxic in vitro, and the latter extract obtained from a location further from these two toxic sampling sites. Then, target organ toxicities were identified following biweekly oral gavage for one month of three soil extracts (0.1% in polyethylene glycol or PEG) compared to vehicle control in male Sprague-Dawley rats (n = 9-10/group). Exposure to extract A significantly increased neutrophils and lymphocytes compared to control. In contrast, all extracts increased plasma α-2 macroglobulin and caused mild-to-moderate lymphocytic proliferation within the spleen white pulp, all indicative of inflammation. Rats exposed to all soil extracts exhibited acute tubular necrosis. Cholinesterase activity was significantly reduced in plasma, but not brain, after exposure to extract A compared to control. Increased hepatic ethoxyresorufin-o-deethylase activity compared to control was observed following exposure to extracts A and B. Exposure to soil extract C in rats showed a prolonged QTc interval in electrocardiography as well as increased brain lipid peroxidation. Candidate contaminants are organochlorine, organophosphate/carbamate pesticides or metabolites. Overall, HepG2 cytotoxicity did not successfully predict the neurotoxicity and cardiotoxicity observed with extract C but was more successful with suspected hydrocarbon toxicities in extracts A and B. Caution should be taken when extrapolating the observation of no effects from in vitro cell culture to in vivo toxicity, and better cell culture lines or assays should be explored.

Bisphenol S Impairs Behaviors through Disturbing Endoplasmic Reticulum Function and Reducing Lipid Levels in the Brain of Zebrafish.

The number of neurotoxic pollutants is increasing, but their mechanism of action is unclear. Here, zebrafish were exposed to 0, 1, 10, and 100 μg/L bisphenol S (BPS) for different durations beginning at 2 h postfertilization (hpf) to explore the neurotoxic mechanisms of BPS. Zebrafish larvae exposed to BPS displayed abnormal neurobehaviors. At 48 and 120 hpf, BPS inhibited yolk lipid consumption and reduced the lipid distribution in the zebrafish brain. Moreover, BPS downregulated the mRNA levels of genes involved in fatty acid elongation in the endoplasmic reticulum (ER) and activated ER stress pathways at 48 and 120 hpf, and KEGG analysis after RNA-seq showed that the protein processing pathway in the ER was significantly enriched after BPS exposure. Exposure to ER toxicants (thapsigargin and tunicamycin), two positive controls, induced neurotoxic effects on zebrafish embryos and larvae similar to those of BPS exposure. These data suggested that BPS and ER toxicants disturbed ER function and reduced brain lipid levels. Continued exposure to BPS into adulthood not only inhibited brain fatty acid elongation and ER function but also caused abnormal swelling of the ER in zebrafish. Our data provide new insights into the neurotoxic mechanism of BPS.

Modulations of bioactive lipids and their receptors in postmortem Alzheimer's disease brains.

Analyses of brain samples from Alzheimer's disease (AD) patients may be expected to help us improve our understanding of the pathogenesis of AD. Bioactive lipids, including sphingolipids, glycerophospholipids, and eicosanoids/related mediators have been demonstrated to exert potent physiological actions and to be involved in the pathogenesis of various human diseases. In this cross-sectional study, we attempted to elucidate the associations of these bioactive lipids with the pathogenesis/pathology of AD through postmortem studies of human brains. We measured the levels of glycerophospholipids, sphingolipids, and eicosanoids/related mediators in the brains of patients with AD (AD brains), patients with Cerad score B (Cerad-b brains), and control subjects (control brains), using a liquid chromatography-mass spectrometry method; we also measured the mRNA levels of specific receptors for these bioactive lipids in the same brain specimens. The levels of several species of sphingomyelins and ceramides were higher in the Cerad-b and AD brains. Levels of several species of lysophosphatidic acids (LPAs), lysophosphatidylcholine, lysophosphatidylserine, lysophosphatidylethanolamine (LPE), lysophosphatidylinositol, phosphatidylcholine, phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol, and phosphatidylglycerol were especially high in the Cerad-b brains, while those of lysophosphatidylglycerol (LPG) were especially high in the AD brains. Several eicosanoids, including metabolites of prostaglandin E2, oxylipins, metabolites of epoxide, and metabolites of DHA and EPA, such as resolvins, were also modulated in the AD brains. Among the lipid mediators, the levels of S1P2, S1P5, LPA1, LPA2, LPA6, P2Y10, GPR174, EP1, DP1, DP2, IP, FP, and TXA2r were lower in the AD and/or Cerad-b brains. The brain levels of ceramides, LPC, LPI, PE, and PS showed strong positive correlations with the Aβ contents, while those of LPG showed rather strong positive correlations with the presence of senile plaques and neurofibrillary tangles. A discriminant analysis revealed that LPG is especially important for AD and the LPE/PE axis is important for Cerad-b. Comprehensive lipidomics, together with the measurement of lipid receptor expression levels provided novel evidence for the associations of bioactive lipids with AD, which is expected to facilitate future translational research and reverse translational research.

Oxidative stress biomarkers and longitudinal changes in human brain imaging across the Alzheimer’s disease continuum

AbstractBackgroundOxidative stress is critical for Alzheimer’s disease (AD) pathophysiology. Brain mitochondrial function, proteins, and lipids are susceptible to oxidative damage caused by reactive oxygen species. In turn, this damage leads to key AD‐like changes in the brain, such as impaired glucose metabolism (i.e., lower fluorodeoxyglucose, or FDG‐PET) and gray matter volume atrophy in AD‐sensitive regions. It is unknown if oxidative stress biomarkers like superoxide dismutase (SOD) proteins track these changes using longitudinal brain imaging data, and what mechanisms may be at work (Figure 1).MethodUsing Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, 192 aged adults (75 unimpaired, 48 MCI, 69 AD) had annual CSF and FDG data available for over 6 years. A two‐phase MRM targeted proteomics panel was used to gauge CSF SOD1 levels from serum. Standard assays in CSF determined Aβ, p‐tau‐181, and total tau. Brain glucose uptake was determined using FDG SUVR calibrated to the pons. Brain volume was examined longitudinally using FreeSurfer.ResultLongitudinally, among SOD1 quartiles (Figure 2), the lowest SOD1 group showed marked hypometabolism among older adults at baseline (R2=0.528, p&lt;.001, “blue line”), but 6 years later instead predicted hypermetabolism (R2=0.389, p&lt;.001). The highest SOD1 group showed no association at baseline but at 6 years later predicted hypometabolism among older adults (R2=0.151, p&lt;.05, “dotted red line”). CSF Aβ and p‐tau‐181 fully mediated these effects (ps&lt;.01), such that lower Aβ and higher p‐tau‐181 over time resulted in higher SOD1 predicting less glucose uptake. Similarly, higher SOD1 was not related to atrophy in AD‐sensitive regions like parahippocampus at baseline, but 5 years later was strongly related to more brain atrophy (R2=0.207,p&lt;.001) (Figure 3), which was mediated by higher CSF total tau (p&lt;.001).ConclusionLike previous reports, we found that SOD1 initially showed neutral or ameliorative patterns, reflecting its classical role in reducing oxidative stress. With increased Aβ or p‐tau‐181 deposition over time, however, SOD1 became a marker of the degree of oxidative damage that may have occurred in neural tissue due to Aβ or tau.

The PIONEER Study: A Multi‐center, Randomized, Double‐blind, Placebo‐controlled Phase 2 Trial of the Effects of T3D‐959 on Safety, Cognition, Function and Plasma Biomarkers in Mild to Moderate Alzheimer’s Disease Subjects: Study Update.

AbstractBackgroundT3D‐959 is a novel (non‐amyloid/non‐tau‐directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). Dysfunctional brain metabolism in AD results from increasing resistance to insulin. Insulin resistance contributes to amyloid plaque formation, tau tangle formation and inflammation. T3D‐959, a brain‐penetrant, small molecule dual nuclear receptor agonist, acts as an insulin sensitizer to overcome insulin resistance to restore and maintain metabolic homeostasis.MethodPIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE = 14‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 15mg, 30mg, 45mg and placebo QD in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function ADCS‐CGIC measures. Secondary outcome measures include DSCT and plasma Aβ 42/40 ratio. Exploratory outcome measures include plasma NfL tau, ptau217 and ptau181, apathy as measured by the NPI, expressive language function as measured by CFT, physical activity as measured by RAPA, plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.ResultPIONEER commenced in March 2021. The study is two‐thirds enrolled and ongoing [See ClinicalTrials.gov identifier NCT04251182]. Blinded, grouped, summary cognitive and functional endpoint data, as well safety data will be presented and discussed.ConclusionPIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD. Topline results are expected in 2023.

Potential of astrocytes in targeting therapy for Alzheimer's disease.

As the most common neurodegenerative disease, Alzheimer's disease (AD) exhibits an incomprehensible pathogenesis, which has led to the continuous failure of drug development in recent years. Although neuronal damage is considered a pathological feature of AD, treatment strategies targeting β-amyloid (Aβ) have not achieved beneficial effects. In-depth research on glial cells has revealed the strong importance and application prospects of astrocytes in the recovery of cognitive functions. This review summarizes the role of astrocytes in AD and the possibility of therapeutic strategies targeting astrocytes. Astrocytes are involved in brain lipid metabolism and can regulate the synthesis and degradation of Aβ to affect the pathology of AD. The tau protein is phosphorylated by astrocytes, and this phosphorylation leads to the formation of neurofibrillary tangles (NFTs). Astrocytes can express a variety of receptors and inflammatory factors and participate in the neuroinflammatory process and the release of proinflammatory mediators. When the glutamate produced by the neurons is not cleared by astrocytes, neurons undergo apoptosis due to blocked cell metabolism. Therapies for astrocytes are highly efficient, and these include stem cell therapy, gene editing technology, astrocyte transformation and chemical drugs. Here, we discuss the advantages and disadvantages of animal and cell models applied to the study of targeted astrocyte therapies. This study helps elucidate the mechanism of astrocytes in AD and promotes the clinical application of potential therapeutic strategies targeting astrocytes.

Lipidomic analysis of isogenic ApoE‐variant iPSC‐derived glia uncovers coupling between inflammatory signaling and lipid metabolism.

AbstractBackgroundApoE is the major genetic risk factor for Alzheimer’s disease and the major regulator of brain lipid metabolism. In the brain ApoE is primarily expressed in glia. How different damaging or protective ApoE variants exactly affects glial lipid metabolism, and/or how this correlates with inflammatory signaling is not known.MethodWe generated iPSC‐derived astrocytes and microglia from isogenic induced pluripotent stem cells (iPSC) with ApoE3/3 (reference), ApoE4/4 (increased risk), ApoE2/2 (decreased risk) and ApoEnull/null (control) genotypes. On these cells we performed unbiased lipidomics and transcriptional profiling to measure inflammatory pathways.ResultWe observed strong accumulation of stored lipids in human ApoE4/4, E2/2 and ApoEnull/null glia compared to ApoE3/3 glia. The composition of the exact species of accumulating lipids differed between ApoE4/4, E2/2 and Enull/null glia, and between astrocytes and microglia. At the transcriptional level, lipid accumulation in some genotypes was associated with increased proinflammatory signaling in astrocytes and microglia.ConclusionsApoE genotypes has a major effect on glial lipid metabolism and specific changes in lipid metabolism associate with inflammatory signaling pathways. Using lipid‐targeting interventions we are currently probing a causal relationship between altered lipid metabolism and downstream increases inflammatory signaling

How Alpha Linolenic Acid May Sustain Blood–Brain Barrier Integrity and Boost Brain Resilience against Alzheimer’s Disease

Cognitive decline, the primary clinical phenotype of Alzheimer's disease (AD), is currently attributed mainly to amyloid and tau protein deposits. However, a growing body of evidence is converging on brain lipids, and blood-brain barrier (BBB) dysfunction, as crucial players involved in AD development. The critical role of lipids metabolism in the brain and its vascular barrier, and its constant modifications particularly throughout AD development, warrants investigation of brain lipid metabolism as a high value therapeutic target. Yet, there is limited knowledge on the biochemical and structural roles of lipids in BBB functionality in AD. Within this framework, we hypothesize that the ApoE4 genotype, strongly linked to AD risk and progression, may be related to altered fatty acids composition in the BBB. Interestingly, alpha linolenic acid (ALA), the precursor of the majoritarian brain component docosahexaenoic acid (DHA), emerges as a potential novel brain savior, acting via BBB functional improvements, and this may be primarily relevant to ApoE4 carriers.

Polyphenol bioavailability and modulatory potential on brain antioxidative markers in C57BL/6 mouse

Background and purpose: Prunus spinose L. is a traditionally consumed, recently scientifically reexamined plant. Brain bioavailability and functionality of polyphenols (PPH) of blackthorn flower extract (PSE) was investigated.Materials and methods: C57BL/6 mice received oral daily repeated doses of 25 mg/kg body weight of total PSE polyphenols for 28 days. Brain concentrations of individual polyphenols from PSE were determined by UPLC/MS on 1st,7th, 14th, 21st, and 28th day. Brain antioxidative defense markers were examined as indicators of functionality after bioaccumulation.Results: A total of 68.7% PPH present in PSE were detected in the brain. Higher (p≤0.05) Cmax/AUClast in the PSE treatment vs. control group was recorded for 59.1% of brain detected compounds, indicating relatively good bioaccumulation in the brain. The highest present compounds in PSE were not necessarily the ones mostly bioapsorbed in the brain. Kaempherols were not significantly distributed, opposite to phenolic acids, quercetins or epicgaloatechin-3-gallate. The compounds with the highest concentrations on 28th day were 4-p-coumaroylquinonic acid, (-)-epicatechin, quercetin-3-O-rutinoside, quercetin–rhamnoside, kaempherol-3-rutinoside and quercetin-3-gucoside. Brain lipid peroxidation (MDA) decreased (p&lt;0.05) on the 21st and 28th day in the PSE group. Increase (p&lt;0.05) in GSH concentration was observed on the 21st and 28th and SOD activity on the 28th day. Catalase activity was unchanged. It could be hypothesized that highest PPH concentration-ratios, caused reduction of lipid peroxidation by radical scavenging and simultaneous induction of glutathione and SOD pathways.Conclusions: Screened compounds could be candidates for examining or creation of brain targeted “neuro-nutriceuticals” polyphenol mixtures.

Altered expression of glycobiology-related genes in Parkinson's disease brain.

The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson's disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been limited studies of expression of glycobiology-related genes in PD brain. The current study was performed as an initial attempt to gain new information regarding potential changes in glycoprotein and glycolipid-related genes in PD by investigating the gene expression status for select glycosyltransferases, sialyltransferases, sialidases, sphingosine kinases, and lysosomal enzymes in the substantia nigra and putamen from patients with PD and neurologically normal controls. Results showed altered expression of glycosyltransferase genes (B3GALT2 and B4GALT1) potentially involved in microglial activation and neuroinflammation, sphingosine-1-phosphate (S1P) modulators (SPHK1, SPHK2, and SGPL1) involved in sphingolipid synthesis and metabolism, polysialyltransferase genes (ST8SIA2 and ST8SIA4) that encode enzymes responsible for polysialic acid (polySia) biosynthesis, and the sialidase NEU4, expression of which has been linked to the clearance of storage materials from lysosomes. The data presented here underscore the complexity of the glycolipid/sphingolipid dysregulation in the PD brain and continued and expanded study of these processes may not only provide a greater understanding of the complex roles of aberrant glycosylation sialylation, and sphingolipid synthesis/metabolism in the pathophysiology of PD but may identify potential druggable targets for PD therapeutics.

Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination

BackgroundAbnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear.MethodsTo determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination.ResultsWe demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice.ConclusionsOur findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.

THE EFFECTS OF MELATONIN, FLUOXETINE AND THEIR COMBINATIONS ON STRESS INDUCED BEHAVIORAL AND COGNITIVE IMPAIRMENTS IN MICE

Objective: Melatonin (Mel) is a hormone with anti-depressant and anti-oxidant features. It is well known that melatonin protects brain cells from reactive oxygen species and that the brain's high oxygen consumption and lipid content make it particularly vulnerable to oxidative stress caused by prolonged stress. This study aims to investigate the effects of melatonin, fluoxetine and their combinations on emotional memory, depression, and anxiety-like behavioral changes induced by immobilization (Imb) stress. Material and Method: 48 male Balb/c mice were divided into eight groups: Cnt (control), Imb, Imb+Mlt, Imb+Flx (fluoxetine), Imb+Mlt+Flx, Mlt, Flx and Mlt+Flx. For seven days in a row, the mice underwent daily immobilization stress for 6 hours. Mice were treated with Mlt (10 mg/kg) and Flx (20 mg/kg). All animals were subjected to the behavioral tests; forced swimming test (FST), open field test (OFT), elevated plus maze (EPM), passive avoidance test (PAT) and hot plate (HP) test. After all behavioral tests, brain tissues were obtained for malondialdehyde level analysis. Result and Discussion: OFT test data showed the time spent in the central zone and the number of entrances to the central area were significantly lower in the Imb group compared to the Cnt group, these were higher in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Also, according to the data obtained from FST, immobile time was significantly higher in the Imb group compared to the Cnt group, it was lower in the Imb+Flx, Imb+Mlt, Imb+Mlt+Flx groups compared to the Imb group. Besides, it was demonstrated that the emotional memory index was statistically higher in the Imb group compared to the Cnt group, and the increasing of memory index returned to normal in the Imb+Mlt and Imb+Mlt+Flx groups with PAT. And also, lipid peroxidation level, which increased in the Imb group, decreased significantly in the Imb+Flx, Imb+Mlt, and Imb+Mlt+Flx groups. As a result, it was observed that melatonin has anti-depressant, anxiolytic, antioxidant effects and normalized emotional memory. Also, melatonin, fluoxetine and their combinations exert similar effects in the present study.

Mass Spectrometry Analysis of the Human Brain Sphingolipidome.

In recent decades, mass spectrometry-based lipidomics has provided a fertile environment for scientific investigations of biochemical and mechanistic processes in biological systems. Notably, this approach has been used to characterize physiological and pathological processes relevant to the central nervous system by identifying changes in the sphingolipid content in the brain, cerebral spinal fluid, and blood plasma. However, despite a preponderance of studies identifying correlations between specific lipids and disease progression, this powerful resource has not yet substantively translated into clinically useful diagnostic assays. Part of this gap may be explained by insufficient depth of the lipidomic profiles in many studies, by lab-to-lab inconsistencies in methodology, and a lack of absolute quantification. These issues limit the identification of specific molecular species and the harmonization of results across independent studies. In this chapter, we contextualize these issues with recent reports identifying correlations between brain lipids and neurological diseases, and we describe the workflow our group has optimized for analysis of the blood plasma sphingolipidome, adapted to the characterization of the human brain tissue.

Feasibility of transient nuclear Overhauser effect imaging in brain at 7 T.

The nuclear Overhauser effect (NOE) quantification from the steady-state NOE imaging suffers from multiple confounding non-NOE-specific sources, including direct saturation, magnetization transfer, and relevant chemical exchange species, and is affected by B0 and B1 + inhomogeneities. The B0 -dependent and B1 + -dependent data needed for deconvolving these confounding effects would increase the scan time substantially, leading to other issues such as patient tolerability. Here, we demonstrate the feasibility of brain lipid mapping using an easily implementable transient NOE (tNOE) approach. This 7T study used a frequency-selective inversion pulse at a range of frequency offsets between 1.0 and 5.0 parts per million (ppm) and -5.0 and -1.0 ppm relative to bulk water peak. This was followed by a fixed/variable mixing time and then a single-shot 2D turbo FLASH readout. The feasibility of tNOE measurements is demonstrated on bovine serum albumin phantoms and healthy human brains. The tNOE measurements from bovine serum albumin phantoms were found to be independent of physiological pH variations. Both bovine serum albumin phantoms and human brains showed broad tNOE contributions centered at approximately -3.5 ppm relative to water peak, with presumably aliphatic moieties in lipids and proteins being the dominant contributors. Less prominent tNOE contributions of approximately +2.5 ppm relative to water, presumably from aromatic moieties, were also detected. These aromatic signals were free from any CEST signals. In this study, we have demonstrated the feasibility of tNOE in human brain at 7 T. This method is more scan-time efficient than steady-state NOE and provides NOE measurement with minimal confounders.