bims-medebr 2023-06-25 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–06–25
33 papers selected by
Regina F. Fernández, Johns Hopkins University

Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes.
Metabolic reprogramming regulates microglial polarization and its role in cerebral ischemia reperfusion.
Apolipoprotein E ε4 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKCε mislocalization in cholinergic neuronal cells.
Intermittent versus continuous ketogenic diet: impact on seizures, gut microbiota and mitochondrial metabolism.
Novel insights into brain lipid metabolism in Alzheimer's disease: oligodendrocytes and white matter abnormalities.
Enlightening brain energy metabolism.
DHCR24 reverses Alzheimer's disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice.
Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases.
Quantitative characterizations of the cholesterol-related pathways in the retina and brain of hamsters.
Ceramide in cerebrovascular diseases.
Amelioration of Cognitive and Olfactory System Deficits in APOE4 Transgenic Mice with DHA Treatment.
Serine Racemase mediates subventricular zone neurogenesis via fatty acid metabolism.
Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson's disease.
GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro.
Behavioral and metabolic and effects of ABCG4 KO in the APPswe,Ind (J9) mouse model of Alzheimer's disease.
Sex differences in plasma lipid profiles of accelerated brain aging.
Lactate as a determinant of neuronal excitability, neuroenergetics and beyond.
Dynamics of Glucose Concentration during the Initiation of Ketogenic Diet Treatment in Children with Refractory Epilepsy: Results of Continuous Glucose Monitoring.
Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.
A novel biallelic frameshift variant in C2orf69 causing developmental regression, seizures, microcephaly, autistic features, and hypertonia.
First insights into region-specific lipidome alterations of prefrontal cortex and hippocampus of mice exposed chronically to microcystins.
Omega-3 Polyunsaturated Fatty Acids Protect Neurological Function After Traumatic Brain Injury by Suppressing Microglial Transformation to the Proinflammatory Phenotype and Activating Exosomal NGF/TrkA Signaling.
Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease.
Mass Spectrometry Imaging Reveals Abnormalities in Cardiolipin Composition and Distribution in Astrocytoma Tumor Tissues.
Microstructural and Metabolic Changes in Normal Aging Human Brain Studied with Combined Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.
Abcd1 deficiency accelerates cuprizone-induced oligodendrocyte loss and axonopathy in a demyelinating mouse model of X-linked adrenoleukodystrophy.
Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.
Astrocyte-mediated mechanisms contribute to traumatic brain injury pathology.
TAT-PEP Alleviated Cognitive Impairment by Alleviating Neuronal Mitochondria Damage and Apoptosis After Cerebral Ischemic Reperfusion Injury.
HMG-CoA Reductase Inhibitors for Traumatic Brain Injury.
Construction of a Brain-specific SLC23A2 Gene Knockout Mice Model.
Modulatory effect of n-3 polyunsaturated fatty acids on depressive-like behaviors in rats with chronic sleep deprivation: potential involvement of melatonin receptor pathway and brain lipidome.
Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis.

bioRxiv. 2023 Jun 07. pii: 2023.06.07.544100. [Epub ahead of print]

Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes.

A T Nelson, M E Cicardi, S S Markandaiah, J Han, N Philp, E Welebob, A R Haeusler, P Pasinelli, G Manfredi, H Kawamata, D Trotti.

The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC) n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.

DOI: https://doi.org/10.1101/2023.06.07.544100
Fundam Clin Pharmacol. 2023 Jun 20.

Metabolic reprogramming regulates microglial polarization and its role in cerebral ischemia reperfusion.

Xiao-Rong Sun, Zi-Meng Yao, Lei Chen, Jie Huang, Shu-Ying Dong.

  The brain is quite sensitive to changes in energy supply because of its high energetic demand. Even small changes in energy metabolism may be the basis of impaired brain function, leading to the occurrence and development of cerebral ischemia/reperfusion (I/R) injury. Abundant evidence supports that metabolic defects of brain energy during the post-reperfusion period, especially low glucose oxidative metabolism and elevated glycolysis levels, which play a crucial role in cerebral I/R pathophysiology. Whereas research on brain energy metabolism dysfunction under the background of cerebral I/R mainly focuses on neurons, the research on the complexity of microglia energy metabolism in cerebral I/R is just emerging. As resident immune cells of the central nervous system, microglia activate rapidly and then transform into an M1 or M2 phenotype to correspond to changes in brain homeostasis during cerebral I/R injury. M1 microglia release proinflammatory factors to promote neuroinflammation, while M2 microglia play a neuroprotective role by secreting anti-inflammatory factors. The abnormal brain microenvironment promotes the metabolic reprogramming of microglia, which further affects the polarization state of microglia and disrupts the dynamic equilibrium of M1/M2, resulting in the aggravation of cerebral I/R injury. Increasing evidence suggests that metabolic reprogramming is a key driver of microglial inflammation. For example, M1 microglia preferentially produce energy through glycolysis, while M2 microglia provide energy primarily through oxidative phosphorylation. In this review, we highlight the emerging significance of regulating microglial energy metabolism in cerebral I/R injury.

Keywords:  cerebral ischemia/reperfusion; metabolic reprogramming; microglia; polarization

DOI:  https://doi.org/10.1111/fcp.12928
Biochim Biophys Acta Mol Basis Dis. 2023 Jun 17. pii: S0925-4439(23)00159-X. [Epub ahead of print] 166793

Apolipoprotein E ε4 triggers neurotoxicity via cholesterol accumulation, acetylcholine dyshomeostasis, and PKCε mislocalization in cholinergic neuronal cells.

Rebecca Piccarducci, Chiara Giacomelli, Maria Sofia Bertilacchi, Andrea Benito-Martinez, Nicoletta Di Giorgi, Simona Daniele, Giovanni Signore, Silvia Rocchiccioli, Marçal Vilar, Laura Marchetti, Claudia Martini.

  The Apolipoprotein E (ApoE) has been known to regulate cholesterol and β-amyloid (Aβ) production, redistribution, and elimination, in the central nervous system (CNS). The ApoE ε4 polymorphic variant leads to impaired brain cholesterol homeostasis and amyloidogenic pathway, thus representing the major risk factor for Alzheimer's Disease (AD). Currently, less is known about the molecular mechanisms connecting ApoE ε4-related cholesterol metabolism and cholinergic system degeneration, one of the main AD pathological features. Herein, in vitro cholinergic neuron models were developed in order to study ApoE neuronal expression and investigate the possible interplay between cholesterol metabolism and cholinergic pathway impairment prompted by ε4 isoform. Particularly, alterations specifically occurring in ApoE ε4-carrying neurons (i.e. increased intracellular ApoE, amyloid precursor protein (APP), and Aβ levels, elevated apoptosis, and reduced cell survival) were recapitulated. ApoE ε4 expression was found to increase intracellular cholesterol accumulation, by regulating the related gene expression, while reducing cholesterol precursor acetyl-CoA, which in turn fuels the acetylcholine (ACh) synthesis route. In parallel, although the ACh intracellular signalling was activated, as demonstrated by the boosted extracellular ACh as well as increased IP3 and Ca2+, the PKCε activation via membrane translocation was surprisingly suppressed, probably explained by the cholesterol overload in ApoE ε4 neuron-like cells. Consequently, the PKC-dependent anti-apoptotic and neuroprotective roles results impaired, reliably adding to other causes of cell death prompted by ApoE ε4. Overall, the obtained data open the way to further critical considerations of ApoE ε4-dependent cholesterol metabolism dysregulation in the alteration of cholinergic pathway, neurotoxicity, and neuronal death.

Keywords:  Apolipoprotein E ε4 genotype; Apoptosis; Cholesterol metabolism; Cholinergic pathway; Neurotoxicity; PKCε

DOI:  https://doi.org/10.1016/j.bbadis.2023.166793
Epilepsia. 2023 Jun 19.

Intermittent versus continuous ketogenic diet: impact on seizures, gut microbiota and mitochondrial metabolism.

Jane Shearer, Morris H Scantlebury, Jong M Rho, Thomas A Tompkins, Chunlong Mu.

  We have previously shown that the ketogenic diet (KD) is effective in reducing the seizures associated with infantile spasms syndrome (ISS) and that this benefit is related to alterations in the gut microbiota. However, it remains unclear whether the efficacy of the KD persists after switching to a normal diet. Employing a neonatal rat model of ISS, we tested the hypothesis that the impact of the KD would diminish when switched to a normal diet. Following epilepsy induction, neonatal rats were divided into two groups: continuous KD for 6 days; and a group fed with KD for 3 days, then a normal diet for 3 days. Spasms frequency, mitochondrial bioenergetics in the hippocampus, and fecal microbiota were evaluated as major readouts. We found that the antiepileptic effect of KD was reversible, as evidenced by the increased spasms frequency in rats that were switched from the KD to a normal diet. The spasms frequency was inversely correlated with mitochondrial bioenergetic function and a set of gut microbes, including Streptococcus thermophilus and Streptococcus azizii. These findings suggest that the antiepileptic and metabolic benefits of the KD decline rapidly in concert with gut microbial alterations in the ISS model.

Keywords:  Gut microbiota; Infantile spasms syndrome; Ketogenic diet; Mitochondrial bioenergetics; Seizures

DOI:  https://doi.org/10.1111/epi.17688
FEBS Open Bio. 2023 Jun 17.

Novel insights into brain lipid metabolism in Alzheimer's disease: oligodendrocytes and white matter abnormalities.

Noe Kawade, Koji Yamanaka.

  Alzheimer's disease (AD) is the most common cause of dementia. A genome-wide association study (GWAS) has shown that several AD risk genes are involved in lipid metabolism. Additionally, epidemiological studies have indicated that the levels of several lipid species are altered in the AD brain. Therefore, lipid metabolism is likely changed in the AD brain, and these alterations might be associated with an exacerbation of AD pathology. Oligodendrocytes are glial cells that produce the myelin sheath, which is a lipid-rich insulator. Dysfunctions of the myelin sheath have been linked to white matter abnormalities observed in the AD brain. Here, we review the lipid composition and metabolism in the brain and myelin and the association between lipidic alterations and AD pathology. We also present the abnormalities in oligodendrocyte lineage cells and white matter observed in AD. Additionally, we discuss metabolic disorders, including obesity, as AD risk factors and the effects of obesity and dietary intake of lipids on the brain.

Keywords:  Alzheimer's disease; lipid metabolism in brain; myelin; oligodendrocytes; white matter

DOI:  https://doi.org/10.1002/2211-5463.13661
Neurobiol Dis. 2023 Jun 21. pii: S0969-9961(23)00226-7. [Epub ahead of print] 106211

Enlightening brain energy metabolism.

L F Barros, I Ruminot, P Y Sandoval, A San Martín.

  Brain tissue metabolism is distributed across several cell types and subcellular compartments, which activate at different times and with different temporal patterns. The introduction of genetically-encoded fluorescent indicators that are imaged using time-lapse microscopy has opened the possibility of studying brain metabolism at cellular and sub-cellular levels. There are indicators for sugars, monocarboxylates, Krebs cycle intermediates, amino acids, cofactors, and energy nucleotides, which inform about relative levels, concentrations and fluxes. This review offers a brief survey of the metabolic indicators that have been validated in brain cells, with some illustrative examples from the literature. Whereas only a small fraction of the metabolome is currently accessible to fluorescent probes, there are grounds to be optimistic about coming developments and the application of these tools to the study of brain disease.

Keywords:  FRET; Flux; Genetically-encoded fluorescent indicator; Metabolite; Single-fluorophore; Time-lapse microscopy

DOI:  https://doi.org/10.1016/j.nbd.2023.106211
Acta Neuropathol Commun. 2023 06 21. 11(1): 102

DHCR24 reverses Alzheimer's disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice.

Wen-Bin Zhang, Yue Huang, Xiao-Rou Guo, Meng-Qi Zhang, Xiang-Shan Yuan, Heng-Bing Zu.

  Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer's disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and involved in AD-related pathological activities. However, DHCR24 as a potential therapeutic target for AD remains to be identified. In present study, we demonstrated the role of DHCR24 in AD by employing delivery of adeno-associated virus carrying DHCR24 gene into the hippocampus of 5xFAD mice. Here, we found that 5xFAD mice had lower levels of cholesterol and DHCR24 expression, and the cholesterol loss was alleviated by DHCR24 overexpression. Surprisingly, the cognitive impairment of 5xFAD mice was significantly reversed after DHCR24-based gene therapy. Moreover, we revealed that DHCR24 knock-in successfully prevented or reversed AD-related pathology in 5xFAD mice, including amyloid-β deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis and apoptosis. In conclusion, our results firstly demonstrated that the potential value of DHCR24-mediated regulation of cellular cholesterol level as a promising treatment for AD.

Keywords:  24-dehydrocholesterol reductase (DHCR24); Alzheimer’s disease; Cholesterol; Gene therapy; Neurodegeneration; Neuroprotection; Pathogenesis

DOI:  https://doi.org/10.1186/s40478-023-01593-y
Cell Mol Neurobiol. 2023 Jun 21.

Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases.

Jifei Miao, Lihua Chen, Xiaojin Pan, Liqing Li, Beibei Zhao, Jiao Lan.

  Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining brain homeostasis. However, in neurodegenerative conditions, microglial cells undergo metabolic reprogramming in response to pathological stimuli, including Aβ plaques, Tau tangles, and α-synuclein aggregates. This metabolic shift is characterized by a transition from oxidative phosphorylation (OXPHOS) to glycolysis, increased glucose uptake, enhanced production of lactate, lipids, and succinate, and upregulation of glycolytic enzymes. These metabolic adaptations result in altered microglial functions, such as amplified inflammatory responses and diminished phagocytic capacity, which exacerbate neurodegeneration. This review highlights recent advances in understanding the molecular mechanisms underlying microglial metabolic reprogramming in neurodegenerative diseases and discusses potential therapeutic strategies targeting microglial metabolism to mitigate neuroinflammation and promote brain health. Microglial Metabolic Reprogramming in Neurodegenerative Diseases This graphical abstract illustrates the metabolic shift in microglial cells in response to pathological stimuli and highlights potential therapeutic strategies targeting microglial metabolism for improved brain health.

Keywords:  Alzheimer's disease; Metabolic reprogramming; Microglia; Multiple sclerosis; Parkinson's disease

DOI:  https://doi.org/10.1007/s10571-023-01376-y
J Lipid Res. 2023 Jun 15. pii: S0022-2275(23)00074-3. [Epub ahead of print] 100401

Quantitative characterizations of the cholesterol-related pathways in the retina and brain of hamsters.

Natalia Mast, Nicole El-Darzi, Yong Li, Irina A Pikuleva.

  The retina and brain are separated from the systemic circulation by the anatomical barriers, which are permeable (the outer blood-retinal barrier) and impermeable (the blood-brain and inner blood-retina barriers) to cholesterol. Herein we investigated whether the whole-body cholesterol maintenance affects cholesterol homeostasis in the retina and brain. We used hamsters, whose whole-body cholesterol handling is more similar to those in humans than in mice and conducted separate administrations of deuterated water and deuterated cholesterol. We assessed the quantitative significance of the retinal and brain pathways of cholesterol input and compared the results with those from our previous studies in mice. The utility of the measurements in the plasma of deuterated 24-hydroxycholesterol, the major cholesterol elimination product from the brain, was investigated as well. We established that despite a 7-fold higher serum LDL to HDL ratio and other cholesterol-related differences, in situ biosynthesis remained the major source of cholesterol for hamster retina, although its quantitative significance was reduced to 53% as compared to 72-78% in mouse retina. In the brain, the principal pathway of cholesterol input was also the same, in situ biosynthesis, accounting for 94% of the total brain cholesterol input (96% in mice); the interspecies differences pertained to the absolute rates of the total cholesterol input and turnover. We documented the correlations between deuterium enrichments of the brain 24-hydroxycholesterol, brain cholesterol, and plasma 24-hydroxycholesterol, which suggested that deuterium enrichment of plasma 24-hydroxycholesteol could be an in vivo marker of cholesterol elimination and turnover in the brain.

Keywords:  24-hydroxycholesterol; brain; cholesterol biosynthesis; deuterated cholesterol; deuterated water; deuterium enrichment; hamster; retina

DOI:  https://doi.org/10.1016/j.jlr.2023.100401
Front Cell Neurosci. 2023 ;17 1191609

Ceramide in cerebrovascular diseases.

Huiqi Yuan, Bin Zhu, Cao Li, Zhigang Zhao.

  Ceramide, a bioactive sphingolipid, serves as an important second messenger in cell signal transduction. Under stressful conditions, it can be generated from de novo synthesis, sphingomyelin hydrolysis, and/or the salvage pathway. The brain is rich in lipids, and abnormal lipid levels are associated with a variety of brain disorders. Cerebrovascular diseases, which are mainly caused by abnormal cerebral blood flow and secondary neurological injury, are the leading causes of death and disability worldwide. There is a growing body of evidence for a close connection between elevated ceramide levels and cerebrovascular diseases, especially stroke and cerebral small vessel disease (CSVD). The increased ceramide has broad effects on different types of brain cells, including endothelial cells, microglia, and neurons. Therefore, strategies that reduce ceramide synthesis, such as modifying sphingomyelinase activity or the rate-limiting enzyme of the de novo synthesis pathway, serine palmitoyltransferase, may represent novel and promising therapeutic approaches to prevent or treat cerebrovascular injury-related diseases.

Keywords:  CSVD; ceramide; cerebrovascular diseases; endothelial cell; microglia; neuron; stroke

DOI:  https://doi.org/10.3389/fncel.2023.1191609
Mol Neurobiol. 2023 Jun 17.

Amelioration of Cognitive and Olfactory System Deficits in APOE4 Transgenic Mice with DHA Treatment.

Laura Martínez González, Adam Bourissai, Mélissa Lessard-Beaudoin, Réjean Lebel, Luc Tremblay, Martin Lepage, Rona K Graham.

  Olfactory dysfunction and atrophy of olfactory brain regions are observed early in mild cognitive impairment and Alzheimer disease. Despite substantial evidence showing neuroprotective effects in MCI/AD with treatment of docosahexaenoic acid (DHA), an omega-3 fatty acid, few studies have assessed DHA and its effects on the olfactory system deficits. We therefore performed structural (MRI), functional (olfactory behavior, novel object recognition), and molecular (markers of apoptosis and inflammation) assessments of APOE4 and wild-type mice ± DHA treatment at 3, 6, and 12 months of age. Our results demonstrate that APOE4 mice treated with the control diet show recognition memory deficits, abnormal olfactory habituation, and discrimination abilities and an increase in IBA-1 immunoreactivity in the olfactory bulb. These phenotypes were not present in APOE4 mice treated with a DHA diet. Alterations in some brain regions' weights and/or volumes were observed in the APOPE4 mice and may be due to caspase activation and/or neuroinflammatory events. These results suggest that the consumption of a diet rich in DHA may provide some benefit to E4 carriers but may not alleviate all symptoms.

Keywords:  APOE4 transgenic mice; Alzheimer disease (AD); Docosahexaenoic acid (DHA); Mild cognitive impairment (MCI); Olfactory dysfunction

DOI:  https://doi.org/10.1007/s12035-023-03401-z
Stem Cell Reports. 2023 Jun 05. pii: S2213-6711(23)00194-7. [Epub ahead of print]

Serine Racemase mediates subventricular zone neurogenesis via fatty acid metabolism.

Robin Roychaudhuri, Hasti Atashi, Solomon H Snyder.

  The adult subventricular zone (SVZ) is a neurogenic niche that continuously produces newborn neurons. Here we show that serine racemase (SR), an enzyme that catalyzes the racemization of L-serine to D-serine and vice versa, affects neurogenesis in the adult SVZ by controlling de novo fatty acid synthesis. Germline and conditional deletion of SR (nestin precursor cells) leads to diminished neurogenesis in the SVZ. Nestin-cre+ mice showed reduced expression of fatty acid synthase and its substrate malonyl-CoA, which are involved in de novo fatty acid synthesis. Global lipidomic analyses revealed significant alterations in different lipid subclasses in nestin-cre+ mice. Decrease in fatty acid synthesis was mediated by phospho Acetyl-CoA Carboxylase that was AMP-activated protein kinase independent. Both L- and D-serine supplementation rescued defects in SVZ neurogenesis, proliferation, and levels of malonyl-CoA in vitro. Our work shows that SR affects adult neurogenesis in the SVZ via lipid metabolism.

Keywords:  D-serine,; L-serine,; adult neurogenesis,; lipid metabolism,; malonyl-CoA; serine racemase,; subventricular zone,

DOI:  https://doi.org/10.1016/j.stemcr.2023.05.015
Theranostics. 2023 ;13(10): 3330-3345

Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson's disease.

Kyung Hwa Kim.

  Rationale: Mitochondrial dysfunction is a key factor in the pathogenesis of Parkinson's disease (PD). Accordingly, many aspects of mitochondrial function have been studied as a putative therapeutic target. Here we present a novel strategy to promote mitochondrial function and protect against Parkinson's disease by the peptide encoded within mitochondrial genome, mitochondria-derived peptide (MDP) humanin (HN). Methods: To test humanin as a potential biomarker in PD, we measured protein levels of circulating humanin from the plasma of PD patients and transgenic or neurotoxic mouse models of PD. Next, we aimed to identify whether HN peptide treatment can regulate its activity or expression. Using mouse models of PD, we assessed HN delivery to the brain via the nasal route of administration. We further revealed a possible mechanism underlying the therapeutic effectiveness of HN peptide for PD using in vitro and ex vivo model of PD. Results: Although the expression of intracellular HN was not correlated with PD, HN treatment itself could induce intracellular HN expression and enhance mitochondrial biogenesis inducing mitochondrial gene expression. After intranasal administration, HN peptide resulted in neuroprotection and behavioral recovery in an animal model of PD. Interestingly, HN peptide following intranasal delivery was found within the brain, mainly via the trigeminal pathways. Mechanistically, HN treatment induced activation of phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway which led to enhanced mitochondrial biogenesis resulting in upregulation of mitochondrial gene including humanin. Conclusion: These data support a novel role of mitochondrial protein humanin in mitochondrial function and neuronal survival against Parkinson's disease, in which humanin treatment is sufficient for stimulating mitochondrial gene expression.

Keywords:  Parkinson's disease; autoinduction; humanin; mitochondria-derived peptide; mitochondrial biogenesis

DOI:  https://doi.org/10.7150/thno.84165
Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Jun 16. pii: S1388-1981(23)00074-4. [Epub ahead of print]1868(9): 159350

GM1 oligosaccharide efficacy against α-synuclein aggregation and toxicity in vitro.

Maria Fazzari, Erika Di Biase, Ludovica Zaccagnini, Alexandre Henriques, Noëlle Callizot, Maria Grazia Ciampa, Laura Mauri, Emma Veronica Carsana, Nicoletta Loberto, Massimo Aureli, Luigi Mari, Monica Civera, Francesca Vasile, Sandro Sonnino, Tim Bartels, Elena Chiricozzi, Giulia Lunghi.

  Fibrillary aggregated α-synuclein represents the neurologic hallmark of Parkinson's disease and is considered to play a causative role in the disease. Although the causes leading to α-synuclein aggregation are not clear, the GM1 ganglioside interaction is recognized to prevent this process. How GM1 exerts these functions is not completely clear, although a primary role of its soluble oligosaccharide (GM1-OS) is emerging. Indeed, we recently identified GM1-OS as the bioactive moiety responsible for GM1 neurotrophic and neuroprotective properties, specifically reverting the parkinsonian phenotype both in in vitro and in vivo models. Here, we report on GM1-OS efficacy against the α-synuclein aggregation and toxicity in vitro. By amyloid seeding aggregation assay and NMR spectroscopy, we demonstrated that GM1-OS was able to prevent both the spontaneous and the prion-like α-synuclein aggregation. Additionally, circular dichroism spectroscopy of recombinant monomeric α-synuclein showed that GM1-OS did not induce any change in α-synuclein secondary structure. Importantly, GM1-OS significantly increased neuronal survival and preserved neurite networks of dopaminergic neurons affected by α-synuclein oligomers, together with a reduction of microglia activation. These data further demonstrate that the ganglioside GM1 acts through its oligosaccharide also in preventing the α-synuclein pathogenic aggregation in Parkinson's disease, opening a perspective window for GM1-OS as drug candidate.

Keywords:  GM1 ganglioside; GM1 oligosaccharide; Parkinson's disease; Plasma membrane signaling; α-Synuclein

DOI:  https://doi.org/10.1016/j.bbalip.2023.159350
Res Sq. 2023 Jun 08. pii: rs.3.rs-3014093. [Epub ahead of print]

Behavioral and metabolic and effects of ABCG4 KO in the APPswe,Ind (J9) mouse model of Alzheimer's disease.

Vincent Fong, Babunageswararao Kanuri, Owen Traubert, Min Lui, Shailendra B Patel.

The pathogenesis of Alzheimer's disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS, and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APP Swe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in Novel object recognition (NOR) and Novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT) and insulin tolerance test (ITT), were also mostly similar between groups with only a few mild metabolic differences noted. Overall these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.

DOI: https://doi.org/10.21203/rs.3.rs-3014093/v1
Neurobiol Aging. 2023 May 26. pii: S0197-4580(23)00105-7. [Epub ahead of print]129 178-184

Sex differences in plasma lipid profiles of accelerated brain aging.

Qu Tian, Brendan A Mitchell, Guray Erus, Christos Davatzikos, Ruin Moaddel, Susan M Resnick, Luigi Ferrucci.

  Lipids are essential components of brain structure and shown to affect brain function. Previous studies have shown that aging men undergo greater brain atrophy than women, but whether the associations between lipids and brain atrophy differ by sex is unclear. We examined sex differences in the associations between circulating lipids by liquid chromatography-tandem mass spectrometry and the progression of MRI-derived brain atrophy index Spatial Patterns of Atrophy for Recognition of Brain Aging (SPARE-BA) over an average of 4.7 (SD = 2.3) years in 214 men and 261 women aged 60 or older who were initially cognitively normal using multivariable linear regression, adjusted for age, race, education, and baseline SPARE-BA. We found significant sex interactions for beta-oxidation rate, short-chain acylcarnitines, long-chain ceramides, and very long-chain triglycerides. Lower beta-oxidation rate and short-chain acylcarnitines in women and higher long-chain ceramides and very long-chain triglycerides in men were associated with faster increases in SPARE-BA (accelerated brain aging). Circulating lipid profiles of accelerated brain aging are sex-specific and vary by lipid classes and structure. Mechanisms underlying these sex-specific lipid profiles of brain aging warrant further investigation.

Keywords:  Brain aging; Lipids; Metabolomics; Plasma; Sex difference

DOI:  https://doi.org/10.1016/j.neurobiolaging.2023.05.013
Neurobiol Dis. 2023 Jun 16. pii: S0969-9961(23)00222-X. [Epub ahead of print] 106207

Lactate as a determinant of neuronal excitability, neuroenergetics and beyond.

Bruno Cauli, Isabelle Dusart, Dongdong Li.

  Over the last decades, lactate has emerged as important energy substrate for the brain fueling of neurons. A growing body of evidence now indicates that it is also a signaling molecule modulating neuronal excitability and activity as well as brain functions. In this review, we will briefly summarize how different cell types produce and release lactate. We will further describe different signaling mechanisms allowing lactate to fine-tune neuronal excitability and activity, and will finally discuss how these mechanisms could cooperate to modulate neuroenergetics and higher order brain functions both in physiological and pathological conditions.

Keywords:  ATP; Astrocytes; HCAR1; Interneurons; K(ATP) channels; NADH; NMDA receptors; Pyramidal cells

DOI:  https://doi.org/10.1016/j.nbd.2023.106207
Epilepsia Open. 2023 Jun 22.

Dynamics of Glucose Concentration during the Initiation of Ketogenic Diet Treatment in Children with Refractory Epilepsy: Results of Continuous Glucose Monitoring.

Klára Brožová, Juraj Michalec, Marek Brabec, Petra Bořilová, Pavel Kohout, Jan Brož.

   OBJECTIVE: The ketogenic diet (KD) is a diet low in carbohydrates and rich in fats which has long been used to treat refractory epilepsy. The metabolic changes related to the KD may increase the risk of hypoglycemia, especially during the first days. The study focused on the impact of KD initiation on glycemia in non-diabetic patients with refractory epilepsy.
METHODS: The subjects were 10 paediatric patients (6 boys, mean age 6,1±2,4 years), treated for intractable epilepsy. Blinded continuous glucose monitoring system (CGM) Dexcom G4 was used.. Patients started on their regular diet in the first 36 hours of monitoring, followed by an increase in lipids intake and a gradual reduction of carbohydrates (relations 1:1;2:1;3:1;3,5:1). We analysed changes in glycemia during fat: non fat ratio changes using a generalized linear model.
RESULTS: The mean monitored time per person was 6 days, 10 hours and 44 minutes. The mean±SD glycemia for the regular diet was 4.84±0.20 mmol/l, for the carbohydrates/fat ratio of 1:1 it was 4.03±0.16, for the ratio of 2:1 it was 3.57±0.10, for the ratio 3:1 it was 3.39±0.13 and for the final ratio of 3.5:1 it was 2.79±0,06 mmol/l (p< 0,001). The portions of time spent in glycemia ≤3.5 mmol/l (≤2.5 mmol/l respectively) were: on the normal diet 0.88% (0.31%) of the monitored period, during 1:1 KD ratio 1.92% (0.95%), during 2:1 ratio 3.18% (1.02%), and during 3:1 and 3.5:1 ratios 13.64% (2.36%) of the monitored time (p<0,05).
SIGNIFICANCE: CGM shows the dynamic of glucose concentration in ketogenic diet treatment initiation. It may be a useful tool to control the effects of this diet on glucose metabolism, especially in hypoglycemia detection.

Keywords:  censored data; continuous glucose monitoring; epilepsy; glucose concentration; ketogenic diet

DOI:  https://doi.org/10.1002/epi4.12778
Pharmacol Res. 2023 Jun 17. pii: S1043-6618(23)00179-2. [Epub ahead of print] 106823

Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.

Giulia Birolini, Marta Valenza, Ilaria Ottonelli, Francesca Talpo, Lucia Minoli, Andrea Cappelleri, Mauro Bombaci, Claudio Caccia, Caterina Canevari, Arianna Trucco, Valerio Leoni, Alice Passoni, Monica Favagrossa, Maria Rosaria Nucera, Laura Colombo, Saverio Paltrinieri, Renzo Bagnati, Jason Thomas Duskey, Riccardo Caraffi, Maria Angela Vandelli, Franco Taroni, Mario Salmona, Eugenio Scanziani, Gerardo Biella, Barbara Ruozi, Giovanni Tosi, Elena Cattaneo.

  Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.

Keywords:  Cholesterol; Huntington's disease; brain delivery; cognitive decline; nanoparticles

DOI:  https://doi.org/10.1016/j.phrs.2023.106823
Am J Med Genet A. 2023 Jun 20.

A novel biallelic frameshift variant in C2orf69 causing developmental regression, seizures, microcephaly, autistic features, and hypertonia.

Elizabeth A Werren, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Akanksha Pandey, Saurabh Vaish, Anusha Raj Kabbur, Bevinahalli N Nandeesh, Anshika Srivastava.

  Combined oxidative phosphorylation deficiency type 53 (COXPD53) is an autosomal recessive neurodevelopmental disorder (NDD) caused by homozygous variants in the gene C2orf69. Here, we report a novel frameshift variant c.187_191dupGCCGA, p.D64Efs*56 identified in an individual with clinical presentation of COXPD53 with developmental regression and autistic features. The variant c.187_191dupGCCGA, p.D64Efs*56 represents the most N-terminal part of C2orf69. Notable clinical features of COXPD53of the proband include developmental delay, developmental regression, seizures, microcephaly, and hypertonia. Structural brain defects of cerebral atrophy, cerebellar atrophy, hypomyelination, and thin corpus callosum were also observed. While we observe strong phenotypic overlap among affected individuals with C2orf69 variants, developmental regression and autistic features have not been previously described in individuals with COXPD53. Together, this case expands the genetic and clinical phenotypic spectrum of C2orf69-associated COXPD53.

Keywords:  C2orf69; COXPD53; neurodevelopmental disorders; novel variant

DOI:  https://doi.org/10.1002/ajmg.a.63310
Environ Int. 2023 07;pii: S0160-4120(23)00291-X. [Epub ahead of print]177 108018

First insights into region-specific lipidome alterations of prefrontal cortex and hippocampus of mice exposed chronically to microcystins.

Jun He, Yang Chen, Shiming Dai, Feng Chen, Yeke Wang, Ting Shi, Liang Chen, Ying Liu, Jun Chen, Ping Xie.

  Microcystins (MCs), a group of most widespread freshwater cyanotoxins that possess strong neurotoxicity, can adversely affect brain structures and functions and are linked to neurodegenerative diseases. Despite the essential role of lipids in brain structures and functions, the brain lipidome profile of mammals exposed to MCs remains unexplored, hindering a clear understanding of the neurotoxic effects of MCs and underlying mechanisms. In this study, we performed untargeted lipidomic profiling using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) on the prefrontal cortex and hippocampus of mice orally exposed to 30 and 300 μg/kg body mass/day of microcystin-leucine arginine (MC-LR) for 180 days to evaluate the impacts of MC-LR on the brain lipidome profile and functions. Our results show that MC-LR resulted in a decline in cognitive parameters, as assessed by the Morris water maze test. Interestingly, apparent neurodegenerative changes were observed in the prefrontal cortex, but not in the hippocampus. Comprehensive lipidomic analyses uncovered profound, region-specific changes in the phospholipid and sphingolipid profile at the levels of lipid subclasses, lipid species, and fatty acyl composition. These changes showed overall decrease trends of lipid content in the prefrontal cortex yet increasing trends in the hippocampus. We identified distinct transcriptional regulations of lipid metabolism and apoptosis by MC-LR in the two regions, which appeared to underlie the neurodegenerative changes. Collectively, this study uncovers region-specific changes in the brain lipidome profile and functions induced by MCs, shedding light on the role of lipid dysfunction in neurotoxicity mechanism of MCs.

Keywords:  Chronic exposure; Hippocampus; Lipidomics; Neurodegeneration; Neurotoxicity; Prefrontal cortex

DOI:  https://doi.org/10.1016/j.envint.2023.108018
Mol Neurobiol. 2023 Jun 17.

Omega-3 Polyunsaturated Fatty Acids Protect Neurological Function After Traumatic Brain Injury by Suppressing Microglial Transformation to the Proinflammatory Phenotype and Activating Exosomal NGF/TrkA Signaling.

Long Lin, Shaorui Zheng, Jinqing Lai, Dan Ye, Qiaomei Huang, Zhe Wu, Xiangrong Chen, Shousen Wang.

  The transformation of microglia to a pro-inflammatory phenotype at the site of traumatic brain injury (TBI) drives the progression of secondary neurodegeneration and irreversible neurological impairment. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to suppress this phenotype transformation, thereby reducing neuroinflammation following TBI, but the molecular mechanisms are unknown. We found that Omega-3 PUFA suppressed the expression of disintegrin metalloproteinase (ADAM17), the enzyme required to convert tumor necrosis factor-α (TNF-α) to the soluble form, thereby inhibiting the TNF-α/NF-κB pathway both in vitro and in a mouse model of TBI. Omega-3 PUFA also prevented the reactive transformation of microglia and promoted the secretion of microglial exosomes containing nerve growth factor (NGF), activating the neuroprotective NGF/TrkA pathway both in culture and TBI model mice. Moreover, Omega-3 PUFA suppressed the pro-apoptotic NGF/P75NTR pathway at the TBI site and reduced apoptotic neuronal death, brain edema, and disruption of the blood-brain barrier. Finally, Omega-3 PUFA preserved sensory and motor function as assessed by two broad-spectrum test batteries. The beneficial effects of Omega-3 PUFA were blocked by an ADAM17 promotor and by a NGF inhibitor, confirming the pathogenic function of ADAM17 and the central neuroprotective role of NGF. Collectively, these findings provide a strong experimental basis for Omega-3 PUFA as a potential clinical treatment for TBI.

Keywords:  ADAM17; Exosome; Microglia; Nerve growth factor; Omega-3 polyunsaturated fatty acid; TNF-α/NF-κB pathway; Traumatic brain injury

DOI:  https://doi.org/10.1007/s12035-023-03419-3
bioRxiv. 2023 Jun 06. pii: 2023.06.04.543525. [Epub ahead of print]

Amyloid β Induces Lipid Droplet-Mediated Microglial Dysfunction in Alzheimer's Disease.

Priya Prakash, Palak Manchanda, Evi Paouri, Kanchan Bisht, Kaushik Sharma, Prageeth R Wijewardhane, Caitlin E Randolph, Matthew G Clark, Jonathan Fine, Elizabeth A Thayer, Alexis Crockett, Nadia Gasmi, Sarah Stanko, Richard A Prayson, Chi Zhang, Dimitrios Davalos, Gaurav Chopra.

Several microglia-expressed genes have emerged as top risk variants for Alzheimer's disease (AD). Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD-risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent upon age and disease progression and is more prominent in the hippocampus in mice and humans. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD-laden microglia exhibited a deficit in Aβ phagocytosis. Unbiased lipidomic analysis identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation. We demonstrate that DGAT2, a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting DGAT2 improved microglial uptake of Aβ. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

DOI: https://doi.org/10.1101/2023.06.04.543525
Cancers (Basel). 2023 May 19. pii: 2842. [Epub ahead of print]15(10):

Mass Spectrometry Imaging Reveals Abnormalities in Cardiolipin Composition and Distribution in Astrocytoma Tumor Tissues.

Anna C Krieger, Luis A Macias, J Clay Goodman, Jennifer S Brodbelt, Livia S Eberlin.

  Cardiolipin (CL) is a mitochondrial lipid with diverse roles in cellular respiration, signaling, and organelle membrane structure. CL content and composition are essential for proper mitochondrial function. Deranged mitochondrial energy production and signaling are key components of glial cell cancers and altered CL molecular species have been observed in mouse brain glial cell xenograft tumors. The objective of this study was to describe CL structural diversity trends in human astrocytoma tumors of varying grades and correlate these trends with histological regions within the heterogeneous astrocytoma microenvironment. To this aim, we applied desorption electrospray ionization coupled with high field asymmetric ion mobility mass spectrometry (DESI-FAIMS-MS) to map CL molecular species in human normal cortex (N = 29), lower-grade astrocytoma (N = 19), and glioblastoma (N = 28) tissues. With this platform, we detected 46 CL species and 12 monolysocardiolipin species from normal cortex samples. CL profiles detected from glioblastoma tissues lacked diversity and abundance of longer chain polyunsaturated fatty acid containing CL species when compared to CL detected from normal and lower-grade tumors. CL profiles correlated with trends in tumor viability and tumor infiltration. Structural characterization of the CL species by tandem MS experiments revealed differences in fatty acid and double bond isomer composition among astrocytoma tissues compared with normal cortex and glioblastoma tissues. The GlioVis platform was used to analyze astrocytoma gene expression data from the CGGA dataset. Decreased expression of several mitochondrial respiratory enzyme encoding-genes was observed for higher-grade versus lower-grade tumors, however no significant difference was observed for cardiolipin synthesis enzyme CRLS1.

Keywords:  cardiolipin; glioma; mass spectrometry imaging; mitochondria; tumor heterogeneity

DOI:  https://doi.org/10.3390/cancers15102842
Clin Neuroradiol. 2023 Jun 19.

Microstructural and Metabolic Changes in Normal Aging Human Brain Studied with Combined Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

N Mahmoudi, M Dadak, P Bronzlik, A A Maudsley, S Sheriff, H Lanfermann, X-Q Ding.

   PURPOSE: This study aimed to detect age-related brain metabolic and microstructural changes in healthy human brains by the use of whole-brain proton magnetic resonance spectroscopic imaging (1H‑MRSI) and quantitative MR imaging (qMRI).
METHODS: In this study, 60 healthy participants with evenly distributed ages (between 21 and 69 years) and sex underwent MRI examinations at 3T including whole-brain 1H‑MRSI. The concentrations of the metabolites N‑acetylaspartate (NAA), choline-containing compounds (Cho), total creatine and phosphocreatine (tCr), glutamine and glutamate (Glx), and myo-inositol (mI), as well as the brain relaxation times T2, T2' and T1 were measured in 12 regions of interest (ROI) in each hemisphere. Correlations between measured parameters and age were estimated with linear regression analysis and Pearson's correlation test.
RESULTS: Significant age-related changes of brain regional metabolite concentrations and tissue relaxation times were found: NAA decreased in eight of twelve ROIs, Cho increased in three ROIs, tCr in four ROIs, and mI in three ROIs. Glx displayed a significant decrease in one ROI and an increase in another ROI. T1 increased in four ROIs and T2 in one ROI, while T2' decreased in two ROIs. A negative correlation of tCr concentrations with T2' relaxation time was found in one ROI as well as the positive correlations of age-related T1 relaxation time with concentrations of tCr, mI, Glx and Cho in another ROI.
CONCLUSION: Normal aging in human brain is associated with coexistent brain regional metabolic alterations and microstructural changes, which may be related to age-related decline in cognitive, affective and psychomotor domains of life in the older population.

Keywords:  Aging; Human brain metabolites; Metabolic imaging and data analysis system; Spin-echo planar spectroscopic imaging; qMRI

DOI:  https://doi.org/10.1007/s00062-023-01300-3
Acta Neuropathol Commun. 2023 06 18. 11(1): 98

Abcd1 deficiency accelerates cuprizone-induced oligodendrocyte loss and axonopathy in a demyelinating mouse model of X-linked adrenoleukodystrophy.

Ksenija Martinović, Jan Bauer, Markus Kunze, Johannes Berger, Sonja Forss-Petter.

  X-linked adrenoleukodystrophy (X-ALD), the most frequent, inherited peroxisomal disease, is caused by mutations in the ABCD1 gene encoding a peroxisomal lipid transporter importing very long-chain fatty acids (VLCFAs) from the cytosol into peroxisomes for degradation via β-oxidation. ABCD1 deficiency results in accumulation of VLCFAs in tissues and body fluids of X-ALD patients with a wide range of phenotypic manifestations. The most severe variant, cerebral X-ALD (CALD) is characterized by progressive inflammation, loss of the myelin-producing oligodendrocytes and demyelination of the cerebral white matter. Whether the oligodendrocyte loss and demyelination in CALD are caused by a primary cell autonomous defect or injury to oligodendrocytes or by a secondary effect of the inflammatory reaction remains unresolved. To address the role of X-ALD oligodendrocytes in demyelinating pathophysiology, we combined the Abcd1 deficient X-ALD mouse model, in which VLCFAs accumulate without spontaneous demyelination, with the cuprizone model of toxic demyelination. In mice, the copper chelator cuprizone induces reproducible demyelination in the corpus callosum, followed by remyelination upon cuprizone removal. By immunohistochemical analyses of oligodendrocytes, myelin, axonal damage and microglia activation during de-and remyelination, we found that the mature oligodendrocytes of Abcd1 KO mice are more susceptible to cuprizone-induced cell death compared to WT mice in the early demyelinating phase. Furthermore, this effect was mirrored by a greater extent of acute axonal damage during demyelination in the KO mice. Abcd1 deficiency did not affect the function of microglia in either phase of the treatment. Also, the proliferation and differentiation of oligodendrocyte precursor cells and remyelination progressed at similar rates in both genotypes. Taken together, our findings point to an effect of Abcd1 deficiency on mature oligodendrocytes and the oligodendrocyte-axon unit, leading to increased vulnerability in the context of a demyelinating insult.

Keywords:  Abcd1 KO; Axonopathy; Cuprizone; Demyelination; Microglia; Oligodendrocytes; Peroxisome; X-ALD

DOI:  https://doi.org/10.1186/s40478-023-01595-w
CNS Neurosci Ther. 2023 Jun 23.

Cerebral glucagon-like peptide-1 receptor activation alleviates traumatic brain injury by glymphatic system regulation in mice.

Chuanxiang Lv, Shuai Han, Zhuang Sha, Mingqi Liu, Shiying Dong, Chunyun Zhang, Zean Li, Kang Zhang, Shouyong Lu, Zhiyang Xu, Li Bie, Rongcai Jiang.

   AIM: We aimed to assess the effects of cerebral glucagon-like peptide-1 receptor (GLP-1R) activation on the glymphatic system and whether this effect was therapeutic for traumatic brain injury (TBI).
METHODS: Immunofluorescence was employed to evaluate glymphatic system function. The blood-brain barrier (BBB) permeability, microvascular basement membrane, and tight junction expression were assessed using Evans blue extravasation, immunofluorescence, and western blot. Immunohistochemistry was performed to assess axonal damage. Neuronal apoptosis was evaluated using Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and western blot. Cognitive function was assessed using behavioral tests.
RESULTS: Cerebral GLP-1R activation restored glymphatic transport following TBI, alleviating BBB disruption and neuronal apoptosis, thereby improving cognitive function following TBI. Glymphatic function suppression by treatment using aquaporin 4 inhibitor TGN-020 abolished the protective effect of the GLP-1R agonist against cognitive impairment.
CONCLUSION: Cerebral GLP-1R activation can effectively ameliorate neuropathological changes and cognitive impairment following TBI; the underlying mechanism could involve the repair of the glymphatic system damaged by TBI.

Keywords:  cognitive impairment; glucagon-like peptide-1 receptor; glymphatic system; traumatic brain injury

DOI:  https://doi.org/10.1111/cns.14308
WIREs Mech Dis. 2023 Jun 18. e1622

Astrocyte-mediated mechanisms contribute to traumatic brain injury pathology.

Carmen Muñoz-Ballester, Stefanie Robel.

  Astrocytes respond to traumatic brain injury (TBI) with changes to their molecular make-up and cell biology, which results in changes in astrocyte function. These changes can be adaptive, initiating repair processes in the brain, or detrimental, causing secondary damage including neuronal death or abnormal neuronal activity. The response of astrocytes to TBI is often-but not always-accompanied by the upregulation of intermediate filaments, including glial fibrillary acidic protein (GFAP) and vimentin. Because GFAP is often upregulated in the context of nervous system disturbance, reactive astrogliosis is sometimes treated as an "all-or-none" process. However, the extent of astrocytes' cellular, molecular, and physiological adjustments is not equal for each TBI type or even for each astrocyte within the same injured brain. Additionally, new research highlights that different neurological injuries and diseases result in entirely distinctive and sometimes divergent astrocyte changes. Thus, extrapolating findings on astrocyte biology from one pathological context to another is problematic. We summarize the current knowledge about astrocyte responses specific to TBI and point out open questions that the field should tackle to better understand how astrocytes shape TBI outcomes. We address the astrocyte response to focal versus diffuse TBI and heterogeneity of reactive astrocytes within the same brain, the role of intermediate filament upregulation, functional changes to astrocyte function including potassium and glutamate homeostasis, blood-brain barrier maintenance and repair, metabolism, and reactive oxygen species detoxification, sex differences, and factors influencing astrocyte proliferation after TBI. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.

Keywords:  TBI; astrocyte; gliosis; heterogeneity; traumatic brain injury

DOI:  https://doi.org/10.1002/wsbm.1622
Mol Neurobiol. 2023 Jun 19.

TAT-PEP Alleviated Cognitive Impairment by Alleviating Neuronal Mitochondria Damage and Apoptosis After Cerebral Ischemic Reperfusion Injury.

Pin Zhao, Jiapo Zhang, JianKe Kuai, Liya Li, Xuying Li, Namin Feng, Hailiang Du, Chen Li, Qiang Wang, Bin Deng.

  Paired immunoglobulin-like receptor B (PirB) was identified as a myelin-associated inhibitory protein (MAIP) receptor that plays a critical role in axonal regeneration, synaptic plasticity and neuronal survival after stroke. In our previous study, a transactivator of transcription-PirB extracellular peptide (TAT-PEP) was generated that can block the interactions between MAIs and PirB. We found that TAT-PEP treatment improved axonal regeneration, CST projection and long-term neurobehavioural recovery after stroke through its effects on PirB-mediated downstream signalling. However, the effect of TAT-PEP on the recovery of cognitive function and the survival of neurons also needs to be investigated. In this study, we investigated whether pirb RNAi could alleviate neuronal injury by inhibiting the expression of PirB following exposure to oxygen-glucose deprivation (OGD) in vitro. In addition, TAT-PEP treatment attenuated the volume of the brain infarct and promoted the recovery of neurobehavioural function and cognitive function. This study also found that TAT-PEP exerts neuroprotection by reducing neuronal degeneration and apoptosis after ischemia-reperfusion injury. In addition, TAT-PEP improved neuron survival and reduced lactate dehydrogenase (LDH) release in vitro. Results also showed that TAT-PEP reduced malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) activity and reduced reactive oxygen species (ROS) accumulation in OGD-injured neurons. The possible mechanism was that TAT-PEP could contribute to the damage of neuronal mitochondria and affect the expression of cleaved caspase 3, Bax and Bcl-2. Our results suggest that PirB overexpression in neurons after ischaemic-reperfusion injury induces neuronal mitochondrial damage, oxidative stress and apoptosis. This study also suggests that TAT-PEP may be a potent neuroprotectant with therapeutic potential for stroke by reducing neuronal oxidative stress, mitochondrial damage, degeneration and apoptosis in ischemic stroke.

Keywords:  Cerebral ischemic reperfusion injury; Cognitive impairment; Neuronal mitochondria; TAT-PEP

DOI:  https://doi.org/10.1007/s12035-023-03404-w
Neurotherapeutics. 2023 Jun 23.

HMG-CoA Reductase Inhibitors for Traumatic Brain Injury.

Kalman Katlowitz, Shankar Gopinath, Jovany Cruz Navarro, Claudia Robertson.

  Traumatic brain injuries (TBIs) are associated with high morbidity and mortality due to both the original insult as well as the destructive biological response that follows. Medical management aims to slow or even halt secondary neurological injury while simultaneously laying the groundwork for recovery. Statins are one class of medications that is showing increased promise in the management of TBI. Used extensively in cardiovascular disease, these drugs were originally developed as competitive inhibitors within the cholesterol production pipeline. They are now used in diverse disease states due to their pleiotropic effects on other biological processes such as inflammation and angiogenesis. Preclinical studies, retrospective reviews, and randomized clinical trials have shown a variety of benefits in the management of TBI, but to date, no large-scale randomized clinical trial has been performed. Despite this limitation, statins' early promise and well-tolerated side effect profile make them a promising new tool in the management of TBIs. More bench and clinical studies are needed to delineate proper treatment regimens as well as understand their true potential.

Keywords:  Cholesterol; Concussion; Inflammation; Statins; Trauma; Traumatic brain injury

DOI:  https://doi.org/10.1007/s13311-023-01399-9
Neuroscience. 2023 Jun 15. pii: S0306-4522(23)00243-9. [Epub ahead of print]524 137-148

Construction of a Brain-specific SLC23A2 Gene Knockout Mice Model.

Bin Cao, Yong Xia, Zengxuan Cai, Ziyu Wang, Chao Tang, Yanhua Song.

  Vitamin C (VC) is a key antioxidant of the Central Nervous System (CNS) and SLC23A2 (SVCT2) is the only transporter that actively transports VC into the brain. While the existing animal models of VC deficiency are in the whole body, the essential role of VC in brain development remains elusive. In our study presented here, the CRISPR/Cas9 technology was applied for the construction of a C57BL/6J-SLC23A2 em1(flox)Smoc mouse model, which was crossed with the Glial fibrillary acidic protein-driven Cre Recombinase (GFAP-Cre) genotype mice to generate a conditional knockout model of SLC23A2(SVCT2) gene in mice brain (GFAP-Cre;SLC23A2 flox/flox) after generations of crossbreeding. Our results showed that the expression of SVCT2 in GFAP-Cre;SLC23A2 flox/flox (Cre;svct2 f/f) mice brain was significantly decreased, and consistently, the expression of Neuronal nuclei antigen (NeuN), Glial fibrillary acidic protein (GFAP), calbindin-28k, brain-derived neurotrophic factor (BDNF) was down-regulated but Ionized calcium binding adapter molecule 1 (Iba-1) was up-regulated in Cre;svct2 f/f mice brain tissues. On the other hand, the levels of Glutathione, Reduced (GSH), myeloperoxidase (MDA), 8-isoprostane, tumor necrosis factor-α (TNF-α) and interleukin-6(IL-6) were significantly increased, but the levels of VC in brain tissue of the model group were decreased in Cre;svct2 f/f mice brain tissues, indicating the protective effect of VC against oxidative stress and inflammation during pregnancy. Thus, the conditional knockout of the SLC23A2 gene in the brain of mouse was successfully established by the CRISPR/Cas9 technology in our study, providing an effective animal model for studying the role of VC in fetal brain development.

Keywords:  CRISPR/Cas9; SLC23A2; Vitamin C; gene knockout; mice model

DOI:  https://doi.org/10.1016/j.neuroscience.2023.05.023
Food Funct. 2023 Jun 19.

Modulatory effect of n-3 polyunsaturated fatty acids on depressive-like behaviors in rats with chronic sleep deprivation: potential involvement of melatonin receptor pathway and brain lipidome.

Chia-Hsuan Chang, Hua-Chien Wu, Yin-Ru Hsieh, Wen-De Lai, Te-Hsuan Tung, Jun-Jie Huang, Wei-Yu Kao, Shih-Yi Huang.

Clinical evidence suggests that a bidirectional relationship is present between sleep loss and psychiatric disorders. Both melatonin receptor agonist ramelteon (RMT) and n-3 polyunsaturated fatty acids (n-3 PUFAs) exhibit antidepressant effects, while their underlying molecular mechanisms might be different. Thus, the present study aims to investigate the add-on effects and possible mechanisms of how RMT and different n-3 PUFAs modulate the melatonin receptor pathway as well as brain lipidome to ameliorate the neuropsychiatric behaviors displayed in rats under chronic sleep deprivation. Thirty-one 6-week-old male Wistar rats were divided into five groups: control (C), sleep deprivation (S), sleep deprivation treated with RMT (SR), sleep deprivation treated with RMT and eicosapentaenoic acid (C20:5n-3, EPA) (SRE), and sleep deprivation treated with RMT and docosahexaenoic acid (C22:6n-3, DHA) (SRD) groups. The results reveal that RMT plus EPA alleviated depressive-like behavior when the rats were subjected to the forced swimming test, whereas RMT plus DHA alleviated anxiety-like behavior when the rats were subjected to the elevated plus maze test. The results of a western blot analysis further revealed that compared with the rats in the S group, those in the SRE and SRD groups exhibited a significantly increased expression of MT2 in the prefrontal cortex, with greater benefits observed in the SRE group. In addition, decreased BDNF and TrkB expression levels were upregulated only in the SRE group. Lipidomic analysis further revealed possible involvement of aberrant lipid metabolism and neuropsychiatric behaviors. RMT plus EPA demonstrated promise as having the effects of reversing the levels of the potential biomarkers of depressive-like behaviors. RMT plus EPA or DHA could ameliorate depressive- and anxiety-like behaviors in sleep-deprived rats through the alteration of the lipidome and MT2 receptor pathway in the brain, whereas EPA and DHA exerted a differential effect.

DOI: https://doi.org/10.1039/d3fo01452e
Transl Neurodegener. 2023 Jun 19. 12(1): 32

Update on the pathological roles of prostaglandin E2 in neurodegeneration in amyotrophic lateral sclerosis.

Hiroshi Nango, Komugi Tsuruta, Hiroko Miyagishi, Yuri Aono, Tadashi Saigusa, Yasuhiro Kosuge.

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E2 (PGE2) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE2 levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE2, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE2 in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE2 biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE2 induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE2-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE2 in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.

Keywords:  Amyotrophic lateral sclerosis; E-prostanoid receptor; Microsomal prostaglandin E synthetase-1; Motor neuron death; Prostaglandin E2

DOI:  https://doi.org/10.1186/s40035-023-00366-w