bims-medebr 2023-04-16 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒04‒16
29 papers selected by
Regina F. Fernández
Johns Hopkins University

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.
Association of dysphagia with altered brain glucose metabolism in Parkinson's disease.
Low glucose induced Alzheimer's disease-like biochemical changes in human induced pluripotent stem cell-derived neurons is due to dysregulated O-GlcNAcylation.
Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.
Alpha-lipoic acid supplementation corrects pathological alterations in cellular models of pantothenate kinase-associated neurodegeneration with residual PANK2 expression levels.
Mitochondrial pyruvate carrier 1 alleviates hypoxic-ischemic brain injury in rats.
Biosynthesis and Significance of Fatty Acids, Glycerophospholipids, and Triacylglycerol in the Processes of Glioblastoma Tumorigenesis.
The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.
Comparison of differential metabolites in brain tissue of aged marmosets and serum of elderly patients after prolonged anesthesia.
Neuronal and Astrocyte Insulin-like Growth Factor-1 Signaling Differentially Modulates Ischemic Stroke Damage.
The role of mitochondrial dynamics in cerebral ischemia-reperfusion injury.
Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct.
Neonatal Exposure to Valproate Induces Long-Term Alterations in Steroid Hormone Levels in the Brain Cortex of Prepubertal Rats.
Neuroprotection and Therapeutic Implications of Creatine Supplementation for Brain Injury Complications.
Neuroprotection of NAD+ and NBP against ischemia/reperfusion brain injury is associated with restoration of sirtuin-regulated metabolic homeostasis.
LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.
Mitochondrial dysfunction as a target in spinal cord injury: intimate correlation between pathological processes and therapeutic approaches.
Analysis of Mouse Brain Sections by Live-cell Time-lapse Confocal Microscopy.
Selected Biomarkers of Oxidative Stress and Energy Metabolism Disorders in Neurological Diseases.
Brain-Derived Major Glycoproteins Are Possible Biomarkers for Altered Metabolism of Cerebrospinal Fluid in Neurological Diseases.
Effects of intermittent fasting on cognitive health and Alzheimer's disease.
Role of the deubiquitinating enzyme UCH-L1 in mitochondrial function.
Enteric Glia and Brain Astroglia: Complex Communication in Health and Disease along the Gut-Brain Axis.
Cardiolipin and OPA1 Team up for Methamphetamine-Induced Locomotor Activity by Promoting Neuronal Mitochondrial Fusion in the Nucleus Accumbens of Mice.
Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice.
Activity-dependent post-translational regulation of palmitoylating and depalmitoylating enzymes in the hippocampus.
Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid-membrane contacts.
On-Tissue Chemical Derivatization for Comprehensive Mapping of Brain Carboxyl and Aldehyde Metabolites by MALDI-MS Imaging.
Effects of Caloric Restriction on Spatial Object Recognition Memory, Hippocampal Neuron Loss and Neuroinflammation in Aged Rats.

J Neuropsychiatry Clin Neurosci. 2023 ;35(2): 104-109

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Wilfredo López-Ojeda, Robin A Hurley.



Keywords:  Brain Metabolism; Brain energy; Ketogenesis; Ketogenic Diet; Metabolic Diseases; Neuroenergetics; Neurological Diseases

DOI:  https://doi.org/10.1176/appi.neuropsych.20230017
CNS Neurosci Ther. 2023 Apr 11.

Association of dysphagia with altered brain glucose metabolism in Parkinson's disease.

Ji Yeon Oh, Eui Jin An, Young Lee, Seung Min Kim, Miju Cheon, Jun Yup Kim.

  AIMS: Dysphagia is a major clinical concern in Parkinson's disease (PD). However, the relationship between the development of phase-specific dysphagia and the regional brain glucose metabolism remains unclear. Our objective was to investigate the distributions of brain glucose metabolism specific to oral and pharyngeal phases of dysphagia in PD.METHODS: In this retrospective cross-sectional study, patients with PD who underwent videofluoroscopic swallowing study (VFSS) and 18 F-fluorodeoxy-glucose positron emission tomography at intervals of <1 month were included. Each swallow was assessed by the binarized Videofluoroscopic Dysphagia Scale with 14 subitems, seven each for the oral and pharyngeal phases. Metabolism mapping was performed by superimposing significant clusters of subitems belonging to each of the two phases using voxel-wise Firth's penalized binary logistic regression model, adjusting for age and PD duration at VFSS.
RESULTS: Eighty-two patients with PD who met the inclusion criteria were included in the analysis. The oral phase dysphagia-specific overlap map showed hypermetabolism in the right inferior temporal gyrus, bilateral cerebellum, superior frontal gyrus, and anterior cingulate cortices. Hypometabolism in the bilateral orbital and triangular parts of the inferior to middle frontal gyrus was also correlated with the occurrence of oral phase dysphagia. The development of pharyngeal phase dysphagia was related to hypermetabolism of posterior aspects of the bilateral parietal lobes, cerebellum, and hypometabolism of the mediodorsal aspects of anterior cingulate and middle to superior frontal gyri.
CONCLUSION: These findings suggest that phase-specific distribution of brain glucose metabolism may explain the dysphagia of PD.

Keywords:  Parkinson's disease; brain glucose metabolism; dysphagia; hypermetabolism; hypometabolism

DOI:  https://doi.org/10.1111/cns.14214
Alzheimers Dement. 2023 Apr 10.

Low glucose induced Alzheimer's disease-like biochemical changes in human induced pluripotent stem cell-derived neurons is due to dysregulated O-GlcNAcylation.

Chia-Wei Huang, Nicholas C Rust, Hsueh-Fu Wu, Amelia Yin, Nadja Zeltner, Hang Yin, Gerald W Hart.

  INTRODUCTION: Sporadic Alzheimer's disease (sAD) is the leading type of dementia. Brain glucose hypometabolism, along with decreased O-GlcNAcylation levels, occurs before the onset of symptoms and correlates with pathogenesis. Heretofore, the mechanisms involved and the roles of O-GlcNAcylation in sAD pathology largely remain unknown due to a lack of human models of sAD.METHODS: Human cortical neurons were generated from pluripotent stem cells (PSCs) and treated with glucose reduction media.
RESULTS: We found a narrow window of glucose concentration that induces sAD-like phenotypes in PSC-derived neurons. With our model, we reveal that dysregulated O-GlcNAc, in part through mitochondrial dysfunction, causes the onset of sAD-like changes. We demonstrate the therapeutic potential of inhibiting O-GlcNAcase in alleviating AD-like biochemical changes.
DISCUSSION: Our results suggest that dysregulated O-GlcNAc might be a direct molecular link between hypometabolism and sAD-like alternations. Moreover, this model can be exploited to explore molecular processes and for drug development.
HIGHLIGHTS: Lowering glucose to a critical level causes AD-like changes in cortical neurons. Defective neuronal structure and function were also recapitulated in current model. Dysregulated O-GlcNAcylation links impaired glucose metabolism to AD-like changes. Mitochondrial abnormalities correlate with O-GlcNAcylation and precede AD-like phenotype. Our model provides a platform to study sAD as a metabolic disease in human neurons.

Keywords:  O-GlcNAcylation; glucose metabolism; human cortical neurons; mitochondrial dysfunction; sporadic Alzheimer's disease

DOI:  https://doi.org/10.1002/alz.13058
J Alzheimers Dis. 2023 Mar 04.

Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.

Yunlong Xu, Fuxiang Zheng, Qi Zhong, Yingjie Zhu.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.

Keywords:  Alzheimer’s disease; amyloid; dementia; ketogenic diet; ketone bodies therapy; ketone body; neuroinflammation; tau protein

DOI:  https://doi.org/10.3233/JAD-230002
Orphanet J Rare Dis. 2023 Apr 12. 18(1): 80

Alpha-lipoic acid supplementation corrects pathological alterations in cellular models of pantothenate kinase-associated neurodegeneration with residual PANK2 expression levels.

Marta Talaverón-Rey, Mónica Álvarez-Córdoba, Irene Villalón-García, Suleva Povea-Cabello, Juan M Suárez-Rivero, David Gómez-Fernández, Ana Romero-González, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Paula Cilleros-Holgado, Diana Reche-López, Rocío Piñero-Pérez, José A Sánchez-Alcázar.

  BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) disorders are a group of neurodegenerative diseases that have in common the accumulation of iron in the basal nuclei of the brain which are essential components of the extrapyramidal system. Frequent symptoms are progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. One of the most prevalent subtypes of NBIA is Pantothenate kinase-associated neurodegeneration (PKAN). It is caused by pathogenic variants in the gene of pantothenate kinase 2 (PANK2) which encodes the enzyme responsible for the first reaction on the coenzyme A (CoA) biosynthesis pathway. Thus, deficient PANK2 activity induces CoA deficiency as well as low expression levels of 4'-phosphopantetheinyl proteins which are essential for mitochondrial metabolism.METHODS: This study is aimed at evaluating the role of alpha-lipoic acid (α-LA) in reversing the pathological alterations in fibroblasts and induced neurons derived from PKAN patients. Iron accumulation, lipid peroxidation, transcript and protein expression levels of PANK2, mitochondrial ACP (mtACP), 4''-phosphopantetheinyl and lipoylated proteins, as well as pyruvate dehydrogenase (PDH) and Complex I activity were examined.
RESULTS: Treatment with α-LA was able to correct all pathological alterations in responsive mutant fibroblasts with residual PANK2 enzyme expression. However, α-LA had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of α-LA in particular pathogenic variants was also confirmed in induced neurons derived from mutant fibroblasts.
CONCLUSIONS: Our results suggest that α-LA treatment can increase the expression levels of PANK2 and reverse the mutant phenotype in PANK2 responsive pathogenic variants. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of α-LA.

Keywords:  4′-phosphopantetheinylation; Acyl carrier protein; Coenzyme A; Induced neurons; Mitochondria; PANK2; PKAN; Pantothenate kinase; Pantothenate kinase-associated neurodegeneration; α-lipoic acid

DOI:  https://doi.org/10.1186/s13023-023-02687-5
Life Sci. 2023 Apr 06. pii: S0024-3205(23)00320-X. [Epub ahead of print] 121686

Mitochondrial pyruvate carrier 1 alleviates hypoxic-ischemic brain injury in rats.

Yue Liu, Yuan Yuan, Yi Yan, Ruyue Wang, Zhaohui Wang, Xiao Liu, Ying Zhang, Jianyu Hua, Yue Wang, Li Zhao.

  AIMS: Mitochondrial dysfunction is a critical pathological change in cerebral ischemia. Mitochondrial pyruvate carrier 1 (MPC1) is a mitochondrial inner membrane protein carrier participating in pyruvate transport. The work is aiming to figure out the effect of MPC1 on cerebral ischemia.MAIN METHODS: Bilateral internal carotid artery embolization (BICAO) rats model and cells model from oxygen glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral ischemia in vivo and in vitro. The effect of MPC1 on cerebral ischemia was detected by imaging, behavioral test, immunofluorescence, flow cytometry, transmission electron microscopy, Western blot and RT-Q-PCR. RNA-sequence (RNA-seq) was applied to explore the potential molecular mechanisms underlying the role of MPC1 in cerebral ischemia.
KEY FINDING: After BICAO or OGD/R treatment, MPC1 expression in ischemic cortical neurons was significantly decreased, and MPC1 deficiency significantly reduced cerebral blood flow, decreased locomotion activities, and exacerbated neuronal injury. Moreover, MPC1 deficiency obviously aggravated oxidative stress, structural disruption and dysfunction of mitochondria, autophagy and calcium overload of ischemic cortical neurons. Interestingly, MPC1 overexpression remarkably reversed neuronal loss and persisting neuronal deficits induced by OGD. Using RNA-seq, 38 MPC1-associated differentially expressed genes were involved in oxidative stress, autophagy and calcium overload. Our results further confirmed that MPC1 could alleviate autophagy via the PI3K/Akt/mTOR pathway in the ischemic cortical neurons.
SIGNIFICANCE: MPC1 may exert neuroprotective effects by attenuating oxidative stress, mitochondrial dysfunction, calcium overload and autophagy during cerebral ischemia. MPC1-related genes identified by RNA-seq may be a novel therapeutic target for cerebral ischemia.

Keywords:  Autophagy; Bilateral internal carotid artery occlusion; Calcium overload; Mitochondrial dysfunction; Mitochondrial pyruvate carrier 1; Oxidative stress

DOI:  https://doi.org/10.1016/j.lfs.2023.121686
Cancers (Basel). 2023 Apr 06. pii: 2183. [Epub ahead of print]15(7):

Biosynthesis and Significance of Fatty Acids, Glycerophospholipids, and Triacylglycerol in the Processes of Glioblastoma Tumorigenesis.

Jan Korbecki, Mateusz Bosiacki, Izabela Gutowska, Dariusz Chlubek, Irena Baranowska-Bosiacka.

  One area of glioblastoma research is the metabolism of tumor cells and detecting differences between tumor and healthy brain tissue metabolism. Here, we review differences in fatty acid metabolism, with a particular focus on the biosynthesis of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA) by fatty acid synthase (FASN), elongases, and desaturases. We also describe the significance of individual fatty acids in glioblastoma tumorigenesis, as well as the importance of glycerophospholipid and triacylglycerol synthesis in this process. Specifically, we show the significance and function of various isoforms of glycerol-3-phosphate acyltransferases (GPAT), 1-acylglycerol-3-phosphate O-acyltransferases (AGPAT), lipins, as well as enzymes involved in the synthesis of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and cardiolipin (CL). This review also highlights the involvement of diacylglycerol O-acyltransferase (DGAT) in triacylglycerol biosynthesis. Due to significant gaps in knowledge, the GEPIA database was utilized to demonstrate the significance of individual enzymes in glioblastoma tumorigenesis. Finally, we also describe the significance of lipid droplets in glioblastoma and the impact of fatty acid synthesis, particularly docosahexaenoic acid (DHA), on cell membrane fluidity and signal transduction from the epidermal growth factor receptor (EGFR).

Keywords:  brain tumor; docosahexaenoic acid; fatty acid; glioblastoma; glycerophospholipids; lipid droplets; polyunsaturated fatty acid; triacylglycerol

DOI:  https://doi.org/10.3390/cancers15072183
Int J Mol Sci. 2023 Mar 27. pii: 6268. [Epub ahead of print]24(7):

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases.

Adeena Shafique, Martina Brughera, Marta Lualdi, Tiziana Alberio.

  Mitochondrial dysfunction and vesicular trafficking alterations have been implicated in the pathogenesis of several neurodegenerative diseases. It has become clear that pathogenetic pathways leading to neurodegeneration are often interconnected. Indeed, growing evidence suggests a concerted contribution of impaired mitophagy and vesicles formation in the dysregulation of neuronal homeostasis, contributing to neuronal cell death. Among the molecular factors involved in the trafficking of vesicles, Ras analog in brain (Rab) proteins seem to play a central role in mitochondrial quality checking and disposal through both canonical PINK1/Parkin-mediated mitophagy and novel alternative pathways. In turn, the lack of proper elimination of dysfunctional mitochondria has emerged as a possible causative/early event in some neurodegenerative diseases. Here, we provide an overview of major findings in recent years highlighting the role of Rab proteins in dysfunctional mitochondrial dynamics and mitophagy, which are characteristic of neurodegenerative diseases. A further effort should be made in the coming years to clarify the sequential order of events and the molecular factors involved in the different processes. A clear cause-effect view of the pathogenetic pathways may help in understanding the molecular basis of neurodegeneration.

Keywords:  Ras analog in brain (Rab); mitophagy; neurodegeneration; vesicular trafficking

DOI:  https://doi.org/10.3390/ijms24076268
Front Mol Neurosci. 2023 ;16 1134239

Comparison of differential metabolites in brain tissue of aged marmosets and serum of elderly patients after prolonged anesthesia.

Fengwei Zhang, Haoli Mao, Jiao Zhu, Ren Zhou, Lei Zhang, Hong Jiang.

  Objective: To compare the differential metabolites in the brain tissue of aged marmosets after long-term anesthesia (≥ 6 h) and the serum of elderly patients by metabolomics methods.Methods: Six aged marmosets (≥ 8 years old) were divided into two groups: anesthesia and control. The aged monkeys in the anesthesia group were induced with 6-8% sevoflurane and 100% oxygen (2 l/min) for 1-2 min and maintained with 1.5-2.5% sevoflurane and 100% oxygen (2 l/min) for 6 h. In the control group (n = 3), anesthesia was only induced under the same conditions for 1-2 min. The prefrontal cortex tissues of the two groups of aged marmosets were collected for metabolomics detection. Twenty-nine elderly patients (≥ 65 years old) who had undergone surgical anesthesia for more than 6 h were enrolled. Serum samples were collected before and on the first day after surgery for metabolomics analysis. Differential metabolites were compared between human serum and marmoset brain tissue.
Results: The changes in lactate and xanthurenic acid in the serum of elderly patients were consistent with those in the brain tissue of aged marmoset monkeys, that is, lactate was up-regulated and xanthurenic acid was down-regulated. However, serum levels of 5-methylterahydrofolic acid and leucine were down-regulated in elderly patients after anesthesia. In contrast, 5-methylterahydrofolic acid and leucine levels were up-regulated in the prefrontal cortex of aged marmosets compared with control marmosets. Furthermore, glycolysis/gluconeogenesis and pentose phosphate pathway were both significantly enriched in the prefrontal cortex of aged marmosets and serum of elderly patients after surgery.
Conclusion: The changes of serum metabolites in elderly patients are not exactly the same as the metabolic changes of brain tissues in aged marmosets. The metabolic changes in serum lactate and xanthurenic acid levels can reflect brain tissue metabolism. The enrichment pathways of differential metabolites in the serum of elderly patients and the brain tissue of aged marmosets were partially the same.

Keywords:  aged marmosets; brain tissue; elderly patients; general anesthesia; metabolites; metabolomics; oxidative stress; serum

DOI:  https://doi.org/10.3389/fnmol.2023.1134239
bioRxiv. 2023 Apr 02. pii: 2023.04.02.535245. [Epub ahead of print]

Neuronal and Astrocyte Insulin-like Growth Factor-1 Signaling Differentially Modulates Ischemic Stroke Damage.

Cellas A Hayes, Nyah I Morgan, Kamryn C Thomas, M Jake Pushie, Akshaya Vijayasankar, Brandon G Ashmore, Kendall Wontor, Miguel A De Leon, Nicole M Ashpole.

Ischemic stroke is a leading cause of death and disability, as therapeutic options for mitigating the long-term deficits precipitated by the event remain limited. Acute administration of the neuroendocrine modulator insulin-like growth factor-1 (IGF-1) attenuates ischemic stroke damage in preclinical models, and clinical studies suggest IGF-1 can reduce the risk of stroke and improve overall outcomes. The cellular mechanism by which IGF-1 exerts this protection is poorly defined, as all cells within the neurovascular unit express the IGF-1 receptor. We hypothesize that the functional regulation of both neurons and astrocytes by IGF-1 is critical in minimizing damage in ischemic stroke. To test this, we utilized inducible astrocyte-specific or neuron-specific transgenic mouse models to selectively reduce IGF-1R in the adult mouse brain prior to photothrombotic stroke. Acute changes in blood brain barrier permeability, microglial activation, systemic inflammation, and biochemical composition of the brain were assessed 3 hours following photothrombosis, and significant protection was observed in mice deficient in neuronal and astrocytic IGF-1R. When the extent of tissue damage and sensorimotor dysfunction was assessed for 3 days following stroke, only the neurological deficit score continued to show improvements, and the extent of improvement was enhanced with additional IGF-1 supplementation. Overall, results indicate that neuronal and astrocytic IGF-1 signaling influences stroke damage but IGF-1 signaling within these individual cell types is not required for minimizing tissue damage or behavioral outcome.

DOI: https://doi.org/10.1101/2023.04.02.535245
Biomed Pharmacother. 2023 Apr 08. pii: S0753-3322(23)00459-6. [Epub ahead of print]162 114671

The role of mitochondrial dynamics in cerebral ischemia-reperfusion injury.

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

  Stroke is one of the leading causes of death and long-term disability worldwide. More than 80 % of strokes are ischemic, caused by an occlusion of cerebral arteries. Without question, restoration of blood supply as soon as possible is the first therapeutic strategy. Nonetheless paradoxically, reperfusion can further aggravate the injury through a series of reactions known as cerebral ischemia-reperfusion injury (CIRI). Mitochondria play a vital role in promoting nerve survival and neurological function recovery and mitochondrial dysfunction is considered one of the characteristics of CIRI. Neurons often die due to oxidative stress and an imbalance in energy metabolism following CIRI, and there is a strong association with mitochondrial dysfunction. Altered mitochondrial dynamics is the first reaction of mitochondrial stress. Mitochondrial dynamics refers to the maintenance of the integrity, distribution, and size of mitochondria as well as their ability to resist external stimuli through a continuous cycle of mitochondrial fission and fusion. Therefore, improving mitochondrial dynamics is a vital means of treating CIRI. This review discusses the relationship between mitochondria and CIRI and emphasizes improving mitochondrial dynamics as a potential therapeutic approach to improve the prognosis of CIRI.

Keywords:  Cerebral ischemia-reperfusion injury; Mitochondria; Mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.biopha.2023.114671
Nat Commun. 2023 Apr 12. 14(1): 2057

Targeting neuronal lysosomal dysfunction caused by β-glucocerebrosidase deficiency with an enzyme-based brain shuttle construct.

Alexandra Gehrlein, Vinod Udayar, Nadia Anastasi, Martino L Morella, Iris Ruf, Doris Brugger, Sophia von der Mark, Ralf Thoma, Arne Rufer, Dominik Heer, Nina Pfahler, Anton Jochner, Jens Niewoehner, Luise Wolf, Matthias Fueth, Martin Ebeling, Roberto Villaseñor, Yanping Zhu, Matthew C Deen, Xiaoyang Shan, Zahra Ehsaei, Verdon Taylor, Ellen Sidransky, David J Vocadlo, Per-Ola Freskgård, Ravi Jagasia.

Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher's disease and are the most common risk factor for Parkinson's disease. Therapies to restore the enzyme's function in the brain hold great promise for treating the neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to β-glucocerebrosidase (referred to as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake and lysosomal efficiency compared to the enzyme alone. In a cellular disease model, GCase-BS rapidly rescues the lysosomal proteome and lipid accumulations beyond known substrates. In a mouse disease model, intravenous injection of GCase-BS leads to a sustained reduction of glucosylsphingosine and can lower neurofilament-light chain plasma levels. Collectively, these findings demonstrate the potential of GCase-BS for treating GBA1-associated lysosomal dysfunction, provide insight into candidate biomarkers, and may ultimately open a promising treatment paradigm for lysosomal storage diseases extending beyond the central nervous system.

DOI: https://doi.org/10.1038/s41467-023-37632-4
Int J Mol Sci. 2023 Apr 03. pii: 6681. [Epub ahead of print]24(7):

Neonatal Exposure to Valproate Induces Long-Term Alterations in Steroid Hormone Levels in the Brain Cortex of Prepubertal Rats.

Soon-Ae Kim, Eun-Hye Jang, Jangjae Lee, Sung-Hee Cho.

  Valproic acid (VPA) is a known drug for treating epilepsy and mood disorders; however, it is not recommended for pregnant women because of its possible teratogenicity. VPA affects neurotransmission and gene expression through epigenetic mechanisms by acting as a histone deacetylase inhibitor and has been used to establish animal models of autism spectrum disorder (ASD). However, studies on the long-term effects of early exposure to VPA on glucocorticoid and neurosteroid synthesis in the brain are lacking. Therefore, this study aimed to investigate the long-term changes in metabolic alterations and gene expression regulation according to sex, using metabolic steroid profiling data from cerebral cortex samples of rats four weeks after VPA exposure (400 mg/kg). In neonatal VPA-exposed models, estradiol levels decreased, and cytochrome P450 19A1 gene (Cyp19a1) expression was reduced in the prepubertal male cortex. Progesterone and allopregnanolone levels decreased, and 3β-hydroxysteroid dehydrogenase 1 gene (Hsd3b1) expression was also downregulated in the prepubertal female cortex. Furthermore, cortisol levels increased, and mRNA expression of the nuclear receptor subfamily 3 group C member 1 gene (Nr3c1) was downregulated in the cortices of both sexes. Unlike the neonatal VPA-exposed models, although a decrease in progestin and estradiol levels was observed in females and males, respectively, no differences were observed in cortisol levels in the cortex tissues of 8-week-old adult rats administered VPA for four weeks. These results indicate that early environmental chemical exposure induces long-term neurosteroid metabolic effects in the brain, with differences according to sex.

Keywords:  autism spectrum disorder; neonatal; neurosteroid; sex-specific difference; steroid hormone; valproic acid

DOI:  https://doi.org/10.3390/ijms24076681
Med J (Ft Sam Houst Tex). 2023 Apr-Jun;(Per 23-4/5/6): 31-38

Neuroprotection and Therapeutic Implications of Creatine Supplementation for Brain Injury Complications.

Jamison M Newman, Timothy B Pekari, David W Van Wyck.

Creatine supplementation has not been researched for Traumatic Brain Injury (TBI) extensively, but studies suggest potential as a neuroprotective agent and potential treatment for brain-injury complications. Patients suffering from TBI experience mitochondrial dysfunction, neuropsychological burden, and deficits in cognitive performance due to malperformance of brain creatine levels, diminished brain Adenosine Triphosphate (ATP) levels, glutamate toxicity, and oxidative stress. In this systemic review, the current available research is reviewed to examine the effects of creatine on common sequalae of TBI within children, adolescents, and mice. Past and present data still lacks the knowledge of creatine supplementation for the adult population and military members during TBI. PubMed was searched for studies which assessed the correlation between creatine supplementation of TBI complications. The search strategy yielded 40 results, of which 15 articles were included in this systemic review. The results of the review supported an apparent understanding creatine does offer an obvious benefit to patients suffering from TBI and post-injury complications under specific guidelines. Time and dose dependent metabolic alterations seem to be only exceptionally prevalent when given as a prophylaxis or if given acutely. Results are only clinically significant after a month of supplementation. Although patients may need many therapeutic treatments to recover from TBI, especially in acute resuscitation, creatine shows superior efficacy as a neuroprotective agent in battling the chronic manifestations which lead to oxidative stress and cognitive function post brain injury.
Front Pharmacol. 2023 ;14 1096533

Neuroprotection of NAD+ and NBP against ischemia/reperfusion brain injury is associated with restoration of sirtuin-regulated metabolic homeostasis.

Xin-Xin Wang, Guang-Hui Mao, Qi-Qi Li, Jie Tang, Hua Zhang, Kang-Lin Wang, Lei Wang, Hong Ni, Rui Sheng, Zheng-Hong Qin.

  Background: Ischemic stroke seriously threatens human health because of high rates of morbidity, mortality and disability. This study compared the effects of nicotinamide adenine dinucleotide (NAD+) and butylphthalide (NBP) on in vitro and in vivo ischemic stroke models. Methods: Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) model was established in mice, and the cultured primary cortical neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cerebral infarct volume, neurobehavioral indices, antioxidant activity, ATP level and lactic acid content were determined. The neuroprotective effects of NAD+ or NBP were compared using sirtuin inhibitor niacinamide (NAM). Results: Intraperitoneal injection of NBP within 4 h or intravenous injection of NAD+ within 1 h after t-MCAO/R significantly reduced the volume of infarcts, cerebral edema, and neurological deficits. Administration of NAD+ and NBP immediately after t-MCAO/R in mice showed similar neuroprotection against acute and long-term ischemic injury. Both NAD+ and NBP significantly inhibited the accumulation of MDA and H2O2 and reduced oxidative stress. NAD+ was superior to NBP in inhibiting lipid oxidation and DNA damage. Furthermore, although both NAD+ and NBP improved the morphology of mitochondrial damage induced by ischemia/reperfusion, NAD+ more effectively reversed the decrease of ATP and increase of lactic acid after ischemia/reperfusion compared with NBP. NAD+ but not NBP treatment significantly upregulated SIRT3 in the brain, but the sirtuin inhibitor NAM could abolish the protective effect of NAD+ and NBP by inhibiting SIRT1 or SIRT3. Conclusions: These results confirmed the protective effects of NAD+ and NBP on cerebral ischemic injury. NBP and NAD+ showed similar antioxidant effects, while NAD+ had better ability in restoring energy metabolism, possibly through upregulating the activity of SIRT1 and SIRT3. The protection provided by NBP against cerebral ischemia/reperfusion may be achieved through SIRT1.

Keywords:  NAD+; NBP; SIRT1; SIRT3; acetylation; cerebral ischemia-reperfusion; mitochondria

DOI:  https://doi.org/10.3389/fphar.2023.1096533
JCI Insight. 2023 Apr 10. pii: e163822. [Epub ahead of print]8(7):

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.

Hiroshi Oue, Yu Yamazaki, Wenhui Qiao, Chen Yuanxin, Yingxue Ren, Aishe Kurti, Francis Shue, Tammee M Parsons, Ralph B Perkerson, Keiji Kawatani, Ni Wang, Skylar C Starling, Bhaskar Roy, Ioana-Emilia Mosneag, Tomonori Aikawa, Marie-Louise Holm, Chia-Chen Liu, Yasuteru Inoue, Patrick M Sullivan, Yan W Asmann, Betty Ys Kim, Guojun Bu, Takahisa Kanekiyo.

  Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.

Keywords:  Alzheimer disease; Dementia; Mouse models; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.163822
Neural Regen Res. 2023 Oct;18(10): 2161-2166

Mitochondrial dysfunction as a target in spinal cord injury: intimate correlation between pathological processes and therapeutic approaches.

Julieta Schmidt, Héctor Ramiro Quintá.

  Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in the locomotor, sensory, and autonomic functions. Damage in the spinal tissue prevents the re-growth of severed axons across the lesion and their reconnection with neuronal targets. Therefore, the absence of spontaneous repair leads to sustained impairment in voluntary control of movement below the injury. For decades, axonal regeneration and reconnection have been considered the opitome of spinal cord injury repair with the goal being the repair of the damaged long motor and sensory tracts in a complex process that involves: (1) resealing injured axons; (2) reconstructing the cytoskeletal structure inside axons; (3) re-establishing healthy growth cones; and (4) assembling axonal cargos. These biological processes require an efficient production of adenosine triphosphate, which is affected by mitochondrial dysfunction after spinal cord injury. From a pathological standpoint, during the secondary stage of spinal cord injury, mitochondrial homeostasis is disrupted, mainly in the distal segments of severed axons. This result in a reduction of adenosine triphosphate levels and subsequent inactivation of adenosine triphosphate-dependent ion pumps required for the regulation of ion concentrations and reuptake of neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, and excitotoxicity. These events are intimately related to the activation of necrotic and apoptotic cell death programs, and further exacerbate the secondary stage of the injury, being a hallmark of spinal cord injury. This is why restoring mitochondrial function during the early stage of secondary injury could represent a potentially effective therapeutic intervention to overcome the motor and sensory failure produced by spinal cord injury. This review discusses the most recent evidence linking mitochondrial dysfunction with axonal regeneration failure in the context of spinal cord injury. It also covers the future of mitochondria-targeted therapeutical approaches, such as antioxidant molecules, removing mitochondrial anchor proteins, and increasing energetic metabolism through creatine treatment. These approaches are intended to enhance functional recovery by promoting axonal regeneration-reconnection after spinal cord injury.

Keywords:  adenosine triphosphate; axonal regeneration; creatine; mitochondria; mitochondria dysfunction; spinal cord injury

DOI:  https://doi.org/10.4103/1673-5374.369094
Bio Protoc. 2023 Apr 05. 13(7): e4648

Analysis of Mouse Brain Sections by Live-cell Time-lapse Confocal Microscopy.

Tao Yang, Ty Hergenreder, Bing Ye.

  The developing cerebral cortex of mammals is generated from nascent pyramidal neurons, which radially migrate from their birthplace in the ventral part of the neural tube to the cortical surface. Subtle aberrations in this process may cause significant changes in cortical structure and lead to developmental neurological disorders. During pyramidal neuron migration, we recently showed that the migrating neuron, which bypasses its last preceding neuron, is critical for its proper positioning and contributes to cerebral cortex thickness. Studying this process requires an imaging system with single-cell resolution and a prolonged observation window. Therefore, we built a system to maintain an organotypic brain slice on the stage of a Leica SP5 confocal microscope, which facilitated high-resolution imaging over a 12-hour time-lapse observation period of cellular events during neuron migration. Here, we share our protocol along with guidelines for overcoming difficulties during the setup. This protocol facilitates the observation of, but is not limited to, neurodevelopmental and pathological processes occurring during neuron migration.

Keywords:  Brain section; Brain slice; Imaging; Live cell; Organotypic; Time-lapse

DOI:  https://doi.org/10.21769/BioProtoc.4648
Mol Neurobiol. 2023 Apr 11.

Selected Biomarkers of Oxidative Stress and Energy Metabolism Disorders in Neurological Diseases.

Izabela Korczowska-Łącka, Mikołaj Hurła, Natalia Banaszek, Dominik Kobylarek, Oliwia Szymanowicz, Wojciech Kozubski, Jolanta Dorszewska.

  Neurological diseases can be broadly divided according to causal factors into circulatory system disorders leading to ischemic stroke; degeneration of the nerve cells leading to neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases, and immune system disorders; bioelectric activity (epileptic) problems; and genetically determined conditions as well as viral and bacterial infections developing inflammation. Regardless of the cause of neurological diseases, they are usually accompanied by disturbances of the central energy in a completely unexplained mechanism. The brain makes up only 2% of the human body's weight; however, while working, it uses as much as 20% of the energy obtained by the body. The energy requirements of the brain are very high, and regulatory mechanisms in the brain operate to ensure adequate neuronal activity. Therefore, an understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving cooperativity between structural and molecular factors in the central nervous system. This article reviewed selected molecular biomarkers of oxidative stress and energy metabolism disorders such as homocysteine, DNA damage such as 8-oxo2dG, genetic variants, and antioxidants such as glutathione in selected neurological diseases including ischemic stroke, AD, PD, and epilepsy. This review summarizes our and others' recent research on oxidative stress in neurological disorders. In the future, the diagnosis and treatment of neurological diseases may be substantially improved by identifying specific early markers of metabolic and energy disorders.

Keywords:  Biomarkers; Energy disturbances; Neurological diseases

DOI:  https://doi.org/10.1007/s12035-023-03329-4
Int J Mol Sci. 2023 Mar 23. pii: 6084. [Epub ahead of print]24(7):

Brain-Derived Major Glycoproteins Are Possible Biomarkers for Altered Metabolism of Cerebrospinal Fluid in Neurological Diseases.

Kyoka Hoshi, Mayumi Kanno, Aya Goto, Yoshikazu Ugawa, Katsutoshi Furukawa, Hiroyuki Arai, Masakazu Miyajima, Koichi Takahashi, Kotaro Hattori, Keiichi Kan, Takashi Saito, Yoshiki Yamaguchi, Takashi Mitsufuji, Nobuo Araki, Yasuhiro Hashimoto.

  Cerebrospinal fluid (CSF) plays an important role in the homeostasis of the brain. We previously reported that CSF major glycoproteins are biosynthesized in the brain, i.e., lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin isoforms carrying unique glycans. Although these glycoproteins are secreted from distinct cell types, their CSF levels have been found to be highly correlated with each other in cases of neurodegenerative disorders. The aim of this study was to examine these marker levels and their correlations in other neurological diseases, such as depression and schizophrenia, and disorders featuring abnormal CSF metabolism, including spontaneous intracranial hypotension (SIH) and idiopathic normal pressure hydrocephalus (iNPH). Brain-derived marker levels were found to be highly correlated with each other in the CSF of depression and schizophrenia patients. SIH is caused by CSF leakage, which is suspected to induce hypovolemia and a compensatory increase in CSF production. In SIH, the brain-derived markers were 2-3-fold higher than in other diseases, and, regardless of their diverse levels, they were found to be correlated with each other. Another abnormality of the CSF metabolism, iNPH, is possibly caused by the reduced absorption of CSF, which secondarily induces CSF accumulation in the ventricle; the excess CSF compresses the brain's parenchyma to induce dementia. One potential treatment is a "shunt operation" to bypass excess CSF from the ventricles to the peritoneal cavity, leading to the attenuation of dementia. After the shunt operation, marker levels began to increase within a week and then further increased by 2-2.5-fold at three, six, and twelve months post-operation, at which point symptoms had gradually attenuated. Notably, the marker levels were found to be correlated with each other in the post-operative period. In conclusion, the brain-derived major glycoprotein markers were highly correlated in the CSF of patients with different neurological diseases, and their correlations were maintained even after surgical intervention. These results suggest that brain-derived proteins could be biomarkers of CSF production.

Keywords:  brain-derived transferrin; cerebrospinal fluid; choroid plexus; neurological diseases; neuron; prostaglandin D2 synthase

DOI:  https://doi.org/10.3390/ijms24076084
Nutr Rev. 2023 Apr 12. pii: nuad021. [Epub ahead of print]

Effects of intermittent fasting on cognitive health and Alzheimer's disease.

Alby Elias, Noushad Padinjakara, Nicola T Lautenschlager.

  OBJECTIVE: Caloric restriction by intermittent fasting produces several metabolic changes, such as increased insulin sensitivity and use of ketone bodies as energy sources. In humans, intermittent fasting has been studied in hypertension, diabetes, and related conditions, but, to date, not as a strategy to reduce the risk of emergent dementia. In this scoping review, the relevance of intermittent fasting as a potential preventive intervention for Alzheimer's dementia is explored.BACKGROUND: The beneficial effects of calorie restriction have been documented in animals and humans. Decreased oxidative stress damage and attenuated inflammatory responses are associated with intermittent fasting. These changes have a favorable impact on the vascular endothelium and stress-induced cellular adaptation.
RESULTS: Physiological alterations associated with fasting have profound implications for pathological mechanisms associated with dementias, particularly Alzheimer's disease. Compared with ad libitum feeding, caloric restriction in animals was associated with a reduction in β-amyloid accumulation, which is the cardinal pathological marker of Alzheimer's disease. Animal studies have demonstrated synaptic adaptations in the hippocampus and enhanced cognitive function after fasting, consistent with these theoretical frameworks. Furthermore, vascular dysfunction plays a crucial role in Alzheimer's disease pathology, and intermittent fasting promotes vascular health.
CONCLUSIONS: These observations lead to a hypothesis that intermittent fasting over the years will potentially reverse or delay the pathological process in Alzheimer's disease.

Keywords:  Alzheimer’s disease; dementia; intermittent fasting; risk

DOI:  https://doi.org/10.1093/nutrit/nuad021
Front Cell Neurosci. 2023 ;17 1149954

Role of the deubiquitinating enzyme UCH-L1 in mitochondrial function.

Alexandre Bouron, Laurence Aubry, Desirée Loreth, Marie-Odile Fauvarque, Catherine Meyer-Schwesinger.



Keywords:  UCH-L1; brain; deubiquitinating enzymes; mitochondria; neurodegeneration; pathology

DOI:  https://doi.org/10.3389/fncel.2023.1149954
Neuroscientist. 2023 Apr 13. 10738584231163460

Enteric Glia and Brain Astroglia: Complex Communication in Health and Disease along the Gut-Brain Axis.

Vanessa D'Antongiovanni, Carolina Pellegrini, Luca Antonioli, Chiara Ippolito, Cristina Segnani, Laura Benvenuti, Antonio D'Amati, Mariella Errede, Daniela Virgintino, Matteo Fornai, Nunzia Bernardini.

  Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative diseases, and related comorbidities. Indeed, patients with IBD can experience neurologic disorders, including depression and cognitive impairment, besides typical intestinal symptoms. In parallel, patients with neurodegenerative disease, such as Parkinson disease and Alzheimer disease, are often characterized by the occurrence of functional gastrointestinal disorders. In this context, enteric glial cells and brain astrocytes are emerging as pivotal players in the initiation/maintenance of neuroinflammatory responses, which appear to contribute to the alterations of intestinal and neurologic functions observed in patients with IBD and neurodegenerative disorders. The present review was conceived to provide a comprehensive and critical overview of the available knowledge on the morphologic, molecular, and functional changes occurring in the enteric glia and brain astroglia in IBDs and neurologic disorders. In addition, our intent is to identify whether such alterations could represent a common denominator involved in the onset of comorbidities associated with the aforementioned disorders. This might help to identify putative targets useful to develop novel pharmacologic approaches for the therapeutic management of such disturbances.

Keywords:  Alzheimer disease; IBD; Parkinson disease; astrocytes; enteric glial cells; gut-brain axis

DOI:  https://doi.org/10.1177/10738584231163460
ACS Chem Neurosci. 2023 Apr 12.

Cardiolipin and OPA1 Team up for Methamphetamine-Induced Locomotor Activity by Promoting Neuronal Mitochondrial Fusion in the Nucleus Accumbens of Mice.

Liang Wang, Qingfan Wei, Rui Xu, Yaxing Chen, Shu Li, Qian Bu, Ying Zhao, Hongchun Li, Yue Zhao, Linhong Jiang, Yuanyuan Chen, Yanping Dai, Yinglan Zhao, Xiaobo Cen.

  Mitochondria are highly dynamic organelles with coordinated cycles of fission and fusion occurring continuously to satisfy the energy demands in the complex architecture of neurons. How mitochondria contribute to addicted drug-induced adaptable mitochondrial networks and neuroplasticity remains largely unknown. Through liquid chromatography-mass spectrometry-based lipidomics, we first analyzed the alteration of the mitochondrial lipidome of three mouse brain areas in methamphetamine (METH)-induced locomotor activity and conditioned place preference. The results showed that METH remodeled the mitochondrial lipidome of the hippocampus, nucleus accumbens (NAc), and striatum in both models. Notably, mitochondrial hallmark lipid cardiolipin (CL) was specifically increased in the NAc in METH-induced hyperlocomotor activity, which was accompanied by an elongated giant mitochondrial morphology. Moreover, METH significantly boosted mitochondrial respiration and ATP generation as well as the copy number of mitochondrial genome DNA in the NAc. By screening the expressions of mitochondrial dynamin-related proteins, we found that repeated METH significantly upregulated the expression of long-form optic atrophy type 1 (L-OPA1) and enhanced the interaction of L-OPA1 with CL, which may promote mitochondrial fusion in the NAc. On the contrary, neuronal OPA1 depletion in the NAc not only recovered the dysregulated mitochondrial morphology and synaptic vesicle distribution induced by METH but also attenuated the psychomotor effect of METH. Collectively, upregulated CL and OPA1 cooperate to mediate METH-induced adaptation of neuronal mitochondrial dynamics in the NAc, which correlates with the psychomotor effect of METH. These findings propose a potential therapeutic approach for METH addiction by inhibiting neuronal mitochondrial fusion.

Keywords:  OPA1; cardiolipin; locomotor activity; methamphetamine; mitochondrial fusion; nucleus Accumbens

DOI:  https://doi.org/10.1021/acschemneuro.2c00709
J Pharmacol Sci. 2023 May;pii: S1347-8613(23)00005-1. [Epub ahead of print]152(1): 30-38

Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice.

Haoyang Wang, Kohji Fukunaga, An Cheng, Yifei Wang, Nariko Arimura, Hiroshi Yoshino, Takuya Sasaki, Ichiro Kawahata.

  Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy.

Keywords:  Dopaminergic neuron; Fatty acid-binding protein 3; HY-11-9; Parkinson's disease; α-Synuclein

DOI:  https://doi.org/10.1016/j.jphs.2023.02.008
J Cell Sci. 2023 Apr 01. pii: jcs260629. [Epub ahead of print]136(7):

Activity-dependent post-translational regulation of palmitoylating and depalmitoylating enzymes in the hippocampus.

Danya Abazari, Angela R Wild, Tian Qiu, Bryan C Dickinson, Shernaz X Bamji.

  Activity-induced changes in protein palmitoylation can regulate the plasticity of synaptic connections, critically impacting learning and memory. Palmitoylation is a reversible post-translational modification regulated by both palmitoyl-acyl transferases that mediate palmitoylation and palmitoyl thioesterases that depalmitoylate proteins. However, it is not clear how fluctuations in synaptic activity can mediate the dynamic palmitoylation of neuronal proteins. Using primary hippocampal cultures, we demonstrate that synaptic activity does not impact the transcription of palmitoylating and depalmitoylating enzymes, changes in thioesterase activity, or post-translational modification of the depalmitoylating enzymes of the ABHD17 family and APT2 (also known as LYPLA2). In contrast, synaptic activity does mediate post-translational modification of the palmitoylating enzymes ZDHHC2, ZDHHC5 and ZDHHC9 (but not ZDHHC8) to influence protein-protein interactions, enzyme stability and enzyme function. Post-translational modifications of the ZDHHC enzymes were also observed in the hippocampus following fear conditioning. Taken together, our findings demonstrate that signaling events activated by synaptic activity largely impact activity of the ZDHHC family of palmitoyl-acyl transferases with less influence on the activity of palmitoyl thioesterases.

Keywords:  Chemical long-term potentiation; Palmitoylation; Post-translational modification; Synapse activity; ZDHHC enzymes

DOI:  https://doi.org/10.1242/jcs.260629
PLoS Comput Biol. 2023 Apr;19(4): e1010992

Ceramide-1-phosphate transfer protein enhances lipid transport by disrupting hydrophobic lipid-membrane contacts.

Julia R Rogers, Phillip L Geissler.

Cellular distributions of the sphingolipid ceramide-1-phosphate (C1P) impact essential biological processes. C1P levels are spatiotemporally regulated by ceramide-1-phosphate transfer protein (CPTP), which efficiently shuttles C1P between organelle membranes. Yet, how CPTP rapidly extracts and inserts C1P into a membrane remains unknown. Here, we devise a multiscale simulation approach to elucidate biophysical details of CPTP-mediated C1P transport. We find that CPTP binds a membrane poised to extract and insert C1P and that membrane binding promotes conformational changes in CPTP that facilitate C1P uptake and release. By significantly disrupting a lipid's local hydrophobic environment in the membrane, CPTP lowers the activation free energy barrier for passive C1P desorption and enhances C1P extraction from the membrane. Upon uptake of C1P, further conformational changes may aid membrane unbinding in a manner reminiscent of the electrostatic switching mechanism used by other lipid transfer proteins. Insertion of C1P into an acceptor membrane, eased by a decrease in membrane order by CPTP, restarts the transfer cycle. Most notably, we provide molecular evidence for CPTP's ability to catalyze C1P extraction by breaking hydrophobic C1P-membrane contacts with compensatory hydrophobic lipid-protein contacts. Our work, thus, provides biophysical insights into how CPTP efficiently traffics C1P between membranes to maintain sphingolipid homeostasis and, additionally, presents a simulation method aptly suited for uncovering the catalytic mechanisms of other lipid transfer proteins.

DOI: https://doi.org/10.1371/journal.pcbi.1010992
J Am Soc Mass Spectrom. 2023 Apr 13.

On-Tissue Chemical Derivatization for Comprehensive Mapping of Brain Carboxyl and Aldehyde Metabolites by MALDI-MS Imaging.

Ibrahim Kaya, Luke S Schembri, Anna Nilsson, Reza Shariatgorji, Sooraj Baijnath, Xiaoqun Zhang, Erwan Bezard, Per Svenningsson, Luke R Odell, Per E Andrén.

The visualization of small metabolites by MALDI mass spectrometry imaging in brain tissue sections is challenging due to low detection sensitivity and high background interference. We present an on-tissue chemical derivatization MALDI mass spectrometry imaging approach for the comprehensive mapping of carboxyls and aldehydes in brain tissue sections. In this approach, the AMPP (1-(4-(aminomethyl)phenyl)pyridin-1-ium chloride) derivatization reagent is used for the covalent charge-tagging of molecules containing carboxylic acid (in the presence of peptide coupling reagents) and aldehydes. This includes free fatty acids and the associated metabolites, fatty aldehydes, dipeptides, neurotoxic reactive aldehydes, amino acids, neurotransmitters and associated metabolites, as well as tricarboxylic acid cycle metabolites. We performed sensitive ultrahigh mass resolution MALDI-MS detection and imaging of various carboxyl- and aldehyde-containing endogenous metabolites simultaneously in rodent brain tissue sections. We verified the AMPP-derivatized metabolites by tandem MS for structural elucidation. This approach allowed us to image numerous aldehydes and carboxyls, including certain metabolites which had been undetectable in brain tissue sections. We also demonstrated the application of on-tissue derivatization to carboxyls and aldehydes in coronal brain tissue sections of a nonhuman primate Parkinson's disease model. Our methodology provides a powerful tool for the sensitive, simultaneous spatial molecular imaging of numerous aldehydes and carboxylic acids during pathological states, including neurodegeneration, in brain tissue.

DOI: https://doi.org/10.1021/jasms.2c00336
Nutrients. 2023 Mar 24. pii: 1572. [Epub ahead of print]15(7):

Effects of Caloric Restriction on Spatial Object Recognition Memory, Hippocampal Neuron Loss and Neuroinflammation in Aged Rats.

Marta Portero-Tresserra, Neus Galofré-López, Elisabet Pallares, Claudia Gimenez-Montes, Carlos Barcia, Roser Granero, Divka Rojic-Becker, Anna Vale-Martínez, Margarita Martí-Nicolovius, Gemma Guillazo-Blanch.

  Age-related neurobiological changes significantly affect hippocampal structure and function, such that the main cognitive impairments associated with aging are related to the integrity of this brain structure, including the deterioration in spatial object recognition (SOR) memory. Previous studies have shown that intrinsic factors such as neuroinflammation, as well as lifestyle factors such as diet, can affect aging-associated brain functions and cognitive performance. In this regard, caloric restriction (CR) produces beneficial effects on health and life expectancy, although its ability to slow down age-dependent effects on cognitive decline and hippocampus (HPC) functioning remains unclear. Therefore, we set out to evaluate the effects of CR on SOR memory in aged male Wistar rats, as well as those on hippocampal neuron loss, neurogenesis and inflammation. The data show that CR in aged rats attenuates the decline in SOR memory, age-associated hippocampal neuron loss, and age-dependent microglial activation. Furthermore, we found a significant reduction in neurogenesis in the dentate gyrus of the old animals relative to adult rats. These findings support the positive effect of CR on SOR memory, suggesting that it dampens hippocampal neuronal loss and reduces proinflammatory activity.

Keywords:  aging; hippocampus; microglia; neurogenesis; spatial memory

DOI:  https://doi.org/10.3390/nu15071572