bims-medebr 2023-12-03 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒12‒03
27 papers selected by
Regina F. Fernández, Johns Hopkins University

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.
The Diagnostic Use of the Plasma Quantification of 24S-Hydroxycholesterol and Other Oxysterols in Neurodegenerative Disease.
Lipidomic Analysis Reveals Differences in the Extent of Remyelination in the Brain and Spinal Cord.
Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease.
NAAG synthetase deficiency has only low influence on pathogenesis in a Canavan disease mouse model.
Regional cerebral metabolism alterations and functional connectivity in individuals with opioid use disorder: An integrated resting-state PET/fMRI study.
Diazepam Binding Inhibitor Control of Eu- and Hypoglycemic Patterns of Ventromedial Hypothalamic Nucleus Glucose-Regulatory Signaling.
Altered anterograde axonal transport of mitochondria in cultured striatal neurons of a knock-in mouse model of Huntington's disease.
24S-Hydroxycholesterol in Neuropsychiatric Diseases: Schizophrenia, Autism Spectrum Disorder, and Bipolar Disorder.
[Beneficial effects of ketogenic diet for Alzheimer's disease management].
Long-term LPS systemic administration leads to memory impairment and disturbance in astrocytic homeostasis.
Ketogenic therapies in Parkinson's disease, Alzheimer's disease, and mild cognitive impairment: An integrative review.
Dynamic T2* relaxometry of hyperpolarized [1-13 C]pyruvate MRI in the human brain and kidneys.
Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease.
Mitochondrial Interaction with Serotonin in Neurobiology and Its Implication in Alzheimer's Disease.
Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features.
CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.
Mass Spectrometry Imaging of Cholesterol and Oxysterols.
AMPK role in epilepsy: a promising therapeutic target?
Allyl Isothiocyanate Maintains DHA-Containing Glycerophospholipids and Ameliorates the Cognitive Function Decline in OVX Mice.
NGLY1 mutations cause protein aggregation in human neurons.
Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.
Effect of consumption of sheep and cow milk on rat brain fatty acid and phospholipid composition.
Quantification of pyruvate in-vitro using mid-infrared spectroscopy: Developing a system for microdialysis monitoring in traumatic brain injury patients.
A Gad2 specific Slc6a8 deletion recapitulates the contextual and cued freezing deficits seen in Slc6a8-/y mice.
Clearance of β-amyloid mediated by autophagy is enhanced by MTORC1 inhibition but not AMPK activation in APP/PSEN1 astrocytes.
Knockout of the intellectual disability-linked gene Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory.

Front Neurosci. 2023 ;17 1297984

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Matin Ramezani, Malika Fernando, Shaun Eslick, Prita R Asih, Sina Shadfar, Ekanayaka M S Bandara, Heidi Hillebrandt, Silochna Meghwar, Maryam Shahriari, Pratishtha Chatterjee, Rohith Thota, Cintia B Dias, Manohar L Garg, Ralph N Martins.

  Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

Keywords:  Alzheimer’s disease; brain energy fuel; circulating biomarkers; disease-modifying therapy; ketogenesis; ketogenic intervention; metabolic interaction

DOI:  https://doi.org/10.3389/fnins.2023.1297984
Adv Exp Med Biol. 2024 ;1440 337-351

The Diagnostic Use of the Plasma Quantification of 24S-Hydroxycholesterol and Other Oxysterols in Neurodegenerative Disease.

Domenico Tripodi, Federica Vitarelli, Simona Spiti, Valerio Leoni.

  Cholesterol regulates fluidity and structure of cellular membranes. The brain is involved in signal transduction, synaptogenesis, and membrane trafficking. An impairment of its metabolism was observed in different neurodegenerative diseases, such as Multiple Sclerosis, Alzheimer, and Huntington diseases. Because of the blood-brain barrier, cholesterol cannot be uptaken from the circulation and all the cholesterol is locally synthetized. The excess cholesterol in neurons is converted into 24S-hydroxycholesterol (24OHC) by the cholesterol 24-hydroxylase (CYP46A1). The plasmatic concentration of 24OHC results in the balance between cerebral production and liver elimination. It is related to the number of metabolically active neurons in the brain. Several factors that affect the brain cholesterol turnover and the liver elimination of oxysterols, the genetic background, nutrition, and lifestyle habits were found to significantly affect plasma levels of 24OHC. Reduced levels of 24OHC were found related to the loss of metabolically active cells and the degree of brain atrophy. The dysfunction of the blood-brain barrier, inflammation, and increased cholesterol turnover might overlap with this progressive reduction giving temporary increased levels of 24OHC.The study of plasma 24OHC is likely to offer an insight into brain cholesterol turnover with a limited diagnostic power.

Keywords:  24S-Hydroxycholesterols; Alzheimer disease; Biomarkers; Cholesterol; Huntington disease; Lipidomic; Mass spectrometry; Multiple sclerosis; Neurodegenerative diseases; Oxysterols; Parkinson disease

DOI:  https://doi.org/10.1007/978-3-031-43883-7_17
J Proteome Res. 2023 Nov 29.

Lipidomic Analysis Reveals Differences in the Extent of Remyelination in the Brain and Spinal Cord.

Nishama De Silva Mohotti, Hiroko Kobayashi, Jenna M Williams, Rashmi Binjawadagi, Michel P Evertsen, Ethan G Christ, Meredith D Hartley.

  During demyelination, lipid-rich myelin debris is released in the central nervous system (CNS) and must be phagocytosed and processed before new myelin can form. Although myelin comprises over 70% lipids, relatively little is known about how the CNS lipidome changes during demyelination and remyelination. In this study, we obtained a longitudinal lipidomic profile of the brain, spinal cord, and serum using a genetic mouse model of demyelination, known as Plp1-iCKO-Myrf. The mass spectrometry data is available at the Metabolomics Workbench, where it has been assigned Study ID ST002958. This model has distinct phases of demyelination and remyelination over the course of 24 weeks, in which loss of motor function peaks during demyelination. Using principal component analysis (PCA) and volcano plots, we have demonstrated that the brain and spinal cord have different remyelination capabilities and that this is reflected in different lipidomic profiles over time. We observed that plasmalogens (ether-linked phosphatidylserine and ether-linked phosphatidylcholine) were elevated specifically during the early stages of active demyelination. In addition, we identified lipids in the brain that were altered when mice were treated with a remyelinating drug, which may be CNS biomarkers of remyelination. The results of this study provide new insights into how the lipidome changes in response to demyelination, which will enable future studies to elucidate mechanisms of lipid regulation during demyelination and remyelination.

Keywords:  demyelination; lipidomics; myelin; remyelination

DOI:  https://doi.org/10.1021/acs.jproteome.3c00443
Front Neurosci. 2023 ;17 1275932

Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease.

Omer Akyol, Sumeyya Akyol, Mei-Chuan Chou, Shioulan Chen, Ching-Kuan Liu, Salih Selek, Jair C Soares, Chu-Huang Chen.

  Alzheimer's disease (AD) and other classes of dementia are important public health problems with overwhelming social, physical, and financial effects for patients, society, and their families and caregivers. The pathophysiology of AD is poorly understood despite the extensive number of clinical and experimental studies. The brain's lipid-rich composition is linked to disturbances in lipid homeostasis, often associated with glucose and lipid abnormalities in various neurodegenerative diseases, including AD. Moreover, elevated low-density lipoprotein (LDL) cholesterol levels may be related to a higher probability of AD. Here, we hypothesize that lipids, and electronegative LDL (L5) in particular, may be involved in the pathophysiology of AD. Although changes in cholesterol, triglyceride, LDL, and glucose levels are seen in AD, the cause remains unknown. We believe that L5-the most electronegative subfraction of LDL-may be a crucial factor in understanding the involvement of lipids in AD pathology. LDL and L5 are internalized by cells through different receptors and mechanisms that trigger separate intracellular pathways. One of the receptors involved in L5 internalization, LOX-1, triggers apoptotic pathways. Aging is associated with dysregulation of lipid homeostasis, and it is believed that alterations in lipid metabolism contribute to the pathogenesis of AD. Proposed mechanisms of lipid dysregulation in AD include mitochondrial dysfunction, blood-brain barrier disease, neuronal signaling, inflammation, and oxidative stress, all of which lead ultimately to memory loss through deficiency of synaptic integration. Several lipid species and their receptors have essential functions in AD pathogenesis and may be potential biomarkers.

Keywords:  Alzheimer’s disease; LDLR; LOX-1; cholesterol; electronegative LDL; lipids

DOI:  https://doi.org/10.3389/fnins.2023.1275932
J Inherit Metab Dis. 2023 Nov 27.

NAAG synthetase deficiency has only low influence on pathogenesis in a Canavan disease mouse model.

Ivonne Becker, Lihua Wang-Eckhardt, Matthias Eckhardt.

  Canavan disease (CD) is a leukodystrophy caused by mutations in the N-acetylaspartate (NAA) hydrolase aspartoacylase (ASPA). Inability to degrade NAA and its accumulation in the brain results in spongiform myelin degeneration. NAA is mainly synthesized by neurons, where it is also a precursor of the neuropeptide N-acetylaspartylglutamate (NAAG). Hydrolysis of this peptide by glutamate carboxypeptidases is an additional source of extracellular NAA besides the instant neuronal release of NAA. This study examines to what extent NAA released from NAAG contributes to NAA accumulation and pathogenesis in the brain of Aspanur7/nur7 mutant mice, an established model of CD. Towards this aim, Aspanur7/nur7 mice with additional deficiencies in NAAG synthetase genes Rimklb and/or Rimkla were generated. Loss of myelin in Aspanur7/nur7 mice was not significantly affected by Rimkla and Rimklb deficiency and there was also no obvious change in the extent of brain vacuolation. Astrogliosis was slightly reduced in the forebrain of Rimkla and Rimklb double deficient Aspanur7/nur7 mice. However, only minor improvements at the behavioral level were found. The brain NAA accumulation in CD mice was, however, not significantly reduced in the absence of NAAG synthesis. In summary, there was only a weak tendency towards reduced pathogenic symptoms in Aspanur7/nur7 mice deficient in NAAG synthesis. Therefore, we conclude that NAAG metabolism has little influence on NAA accumulation in Aspanur7/nur7 mice and development of pathological symptoms in CD.

Keywords:  Canavan disease; N-acetylaspartate; N-xacetylaspartylglutamate; aspartoacylase; leukodystrophy; spongiform degeneration

DOI:  https://doi.org/10.1002/jimd.12693
J Psychiatr Res. 2023 Nov 19. pii: S0022-3956(23)00523-X. [Epub ahead of print]169 126-133

Regional cerebral metabolism alterations and functional connectivity in individuals with opioid use disorder: An integrated resting-state PET/fMRI study.

Long Jin, Menghui Yuan, Wei Zhang, Lei Wang, Jiajie Chen, Yixin Wei, Yunbo Li, Zhirui Guo, Qianrong Bai, Wei Wang, Longxiao Wei, Qiang Li.

  Individuals with opioid use disorder (OUD) have been reported to show abnormal brain metabolism and impaired coupling among brain networks such as the default mode network (DMN), salience network (SN), and executive control network (ECN). However, the characteristics of brain glucose metabolism and its related functions in the brain networks in individuals with OUD remain unknown. Thirty-six individuals with OUD and thirty matched healthy controls (HCs) were recruited in this integrated positron emission tomography/magnetic resonance imaging (PET/MRI) study. Differences in glucose metabolism were analyzed by using 18F-fluorodeoxyglucose (18F-FDG), and the corresponding coupling characteristics of the individuals with OUD were also analyzed. The individuals with OUD showed widespread bilateral hypometabolism in the middle temporal gyrus (MTG), superior temporal gyrus, angular gyrus, supramarginal gyrus, inferior parietal lobe, Rolandic operculum, and left insula, but obvious hypermetabolism in the brainstem and left cerebellum. Meanwhile, in individuals with OUD, the hypometabolism of right MTG which is included in the DMN was accompanied by decreased coupling with the left superior frontal gyrus and right superior parietal gyrus which are included in the ECN. Furthermore, individuals with OUD showed a positive correlation between the duration of heroin use and glucose metabolism of the left MTG. The individuals with OUD were characterized by widespread bilateral hypometabolism in the temporal and parietal regions but obvious hypermetabolism in the brainstem and left cerebellum. The results suggest that the hypometabolism in the temporal and parietal regions might be related to DMN dysfunction and the hypermetabolism in the brainstem and left cerebellum may be compensate for other brain regions showing hypometabolism. In particular, hypometabolism in the self-referential-related DMN regions in OUD might attenuate their relationships with the inhibitory-control-related ECN regions. These findings highlight the importance of evaluating the metabolic and functional profiles of the right MTG in future studies on the treatment of OUD.

Keywords:  Functional connectivity; Glucose metabolism; Heroin; Magnetic resonance imaging; Opioid use disorder; Positron emission tomography

DOI:  https://doi.org/10.1016/j.jpsychires.2023.11.015
ASN Neuro. 2023 Jan-Dec;15:15 17590914231214116

Diazepam Binding Inhibitor Control of Eu- and Hypoglycemic Patterns of Ventromedial Hypothalamic Nucleus Glucose-Regulatory Signaling.

Sagor C Roy, Subash Sapkota, Madhu Babu Pasula, Khaggeswar Bheemanapally, Karen P Briski.

  Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory γ-aminobutyric acid (GABA) and nitric oxide transmission. The current research used newly developed capillary zone electrophoresis-mass spectrometry methods to investigate hypoglycemia effects on VMN octadecaneuropeptide content, along with gene knockdown tools to determine if octadecaneuropeptide signaling regulates these transmitters during eu- and/or hypoglycemia. Hypoglycemia caused dissimilar adjustments in the octadecaneuropeptide precursor, i.e., diazepam-binding-inhibitor and octadecaneuropeptide levels in dorsomedial versus ventrolateral VMN. Intra-VMN diazepam-binding-inhibitor siRNA administration decreased baseline 67 and 65 kDa glutamate decarboxylase mRNA levels in GABAergic neurons laser-microdissected from each location, but only affected hypoglycemic transcript expression in ventrolateral VMN. This knockdown therapy imposed dissimilar effects on eu- and hypoglycemic glucokinase and 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) gene profiles in dorsomedial versus ventrolateral GABAergic neurons. Diazepam-binding-inhibitor gene silencing up-regulated baseline (dorsomedial) or hypoglycemic (ventrolateral) nitrergic neuron neuronal nitric oxide synthase mRNA profiles. Baseline nitrergic cell glucokinase mRNA was up- (ventrolateral) or down- (dorsomedial) regulated by diazepam-binding-inhibitor siRNA, but knockdown enhanced hypoglycemic profiles in both sites. Nitrergic nerve cell AMPKα1 and -α2 transcripts exhibited division-specific responses to this genetic manipulation during eu- and hypoglycemia. Results document the utility of capillary zone electrophoresis-mass spectrometric tools for quantification of ODN in small-volume brain tissue samples. Data show that hypoglycemia has dissimilar effects on ODN signaling in the two major neuroanatomical divisions of the VMN and that this glio-peptide imposes differential control of glucose-regulatory neurotransmission in the VMNdm versus VMNvl during eu- and hypoglycemia.

Keywords:  Diazepam-binding inhibitor; QTRAP CESI-MS/MS; glutamate decarboxylases; insulin-induced hypoglycemia; sex differences; siRNA gene knockdown

DOI:  https://doi.org/10.1177/17590914231214116
Biochem Biophys Res Commun. 2023 Nov 18. pii: S0006-291X(23)01340-2. [Epub ahead of print]691 149246

Altered anterograde axonal transport of mitochondria in cultured striatal neurons of a knock-in mouse model of Huntington's disease.

Chao Wu, Haoran Yin, Songdi Fu, Hanna Yoo, Min Zhang, Hyokeun Park.

  Huntington's disease (HD) is a progressive genetic neurodegenerative disease caused by an abnormal expansion of a cytosine-adenine-guanine trinucleotide repeat in the huntingtin gene. One pathological feature of HD is neuronal loss in the striatum. Despite many efforts, mechanisms underlying neuronal loss in HD striatum remain elusive. It was suggested that the mutant huntingtin protein interacts mitochondrial proteins and causes mitochondrial dysfunction in striatal neurons. However, whether axonal transport of mitochondria is altered in HD striatal neurons remains controversial. Here, we examined axonal transport of single mitochondria labelled with Mito-DsRed2 in cultured striatal neurons of zQ175 knock-in mice (a knock-in mouse model of HD). We observed decreased anterograde axonal transport of proximal mitochondria in HD striatal neurons compared with wild-type (WT) striatal neurons. Decreased anterograde transport in HD striatal neurons was prevented by overexpressing mitochondrial Rho GTPase 1 (Miro1). Our results offer a new insight into mechanisms underlying neuronal loss in the striatum in HD.

Keywords:  Axonal transport; Huntington's disease; Miro1; Mitochondria; Neurodegenerative disease; Real-time imaging

DOI:  https://doi.org/10.1016/j.bbrc.2023.149246
Adv Exp Med Biol. 2024 ;1440 293-304

24S-Hydroxycholesterol in Neuropsychiatric Diseases: Schizophrenia, Autism Spectrum Disorder, and Bipolar Disorder.

Meriam Messedi, Fatma Makni-Ayadi.

  Neuropsychiatric diseases (NPDs) are severe, debilitating psychiatric conditions that affect the nervous system. These are among the most challenging disorders in medicine. Some examples include Alzheimer's, anxiety disorders, autism spectrum disorder, bipolar disorder, and schizophrenia. NPDs represent an ever-increasing burden on public health and are prevalent throughout the world. For most of these diseases, the particular etiopathogeneses are still enigmatic. NPDs are also associated with structural and functional changes in the brain, along with altered neurotransmitter and neuroendocrine systems.Approximately 25% of the total human body cholesterol is located in the brain. Its involvement in neuronal functions starts in the early growth stages and remains important throughout adulthood. It is also an integral part of the neuronal membrane, ensuring membrane lipid organization and regulating membrane fluidity. The main mechanism for removing cholesterol from the brain is cholesterol 24-hydroxylation by cytochrome P450 46A1 (CYP46A1), an enzyme specifically found in the central nervous system. Although research on 24S-OHC and its role in neuropsychiatric diseases is still in its early stages, this oxidized cholesterol metabolite is thought to play a crucial role in the etiology of NPDs. 24S-OHC can affect neurons, astrocytes, oligodendrocytes, and vascular cells. In addition to regulating the homeostasis of cholesterol in the brain, this oxysterol is involved in neurotransmission, oxidative stress, and inflammation. The role of 24S-OHC in NPDs has been found to be controversial in terms of the findings so far. There are several intriguing discrepancies in the data gathered so far regarding 24S-OHC and NPDs. In fact, 24S-OHC levels were reported to have decreased in a number of NPDs and increased in others.Hence, in this chapter, we first summarize the available data regarding 24S-OHC as a biomarker in NPDs, including schizophrenia, autism spectrum disorder, and bipolar disorder. Then, we present a brief synopsis of the pharmacological targeting of 24S-OHC levels through the modulation of CYP46A1 activity.

Keywords:  24S-hydroxycholesterol; Autism spectrum disorder; Bipolar disorder; Brain; CYP46A1; Neuropsychiatric diseases; Schizophrenia

DOI:  https://doi.org/10.1007/978-3-031-43883-7_15
Biol Aujourdhui. 2023 ;217(3-4): 253-263

[Beneficial effects of ketogenic diet for Alzheimer's disease management].

Anouk Charlot, Alix Lernould, Irène Plus, Joffrey Zoll.

  Alzheimer's disease (AD) is a neurodegenerative disease that affects almost 1 million people in France and 55 million in the world. This pathology is a global health preoccupation because of the lack of efficient curative treatment and the increase of its prevalence. During the last decade, the comprehension of pathophysiological mechanisms involved in AD have been improved. Amyloid plaques and neurofibrillary tangles accumulation are characteristic of Alzheimer's brain patients, accompanied by increased brain inflammation and oxidative stress, impaired cerebral metabolism of glucose and mitochondrial function. Treatment of AD includes different approaches, as pharmacology, psychology support, physiotherapy, and speech therapy. However, these interventions do not have a curative effect, but only compensatory on the disease. Ketogenic diet (KD), a low-carbohydrates and high-fat diet, associated with a medium-chain triglycerides intake (MCTs) might induce benefices for Alzheimer disease patients. Carbohydrate restriction and MCTs promotes the production of ketone bodies from fatty acid degradation. These metabolites replacing glucose, serve the brain as energetic substrates, and induce neuroprotective effects. Such a nutritional support might slow down the disease progression and improve cognitive abilities of patients. This review aims to examine the neuroprotective mechanisms of KD in AD progression and describes the advantages and limitations of KD as a therapeutic strategy.

Keywords:  Alzheimer’s disease; corps cétoniques; glucose; ketogenic diet; ketone bodies; maladie d’Alzheimer; medium chain triglycerides; régime cétogène; triglycérides à chaîne moyenne

DOI:  https://doi.org/10.1051/jbio/2023031
Neurotoxicology. 2023 Nov 23. pii: S0161-813X(23)00148-1. [Epub ahead of print]99 322-331

Long-term LPS systemic administration leads to memory impairment and disturbance in astrocytic homeostasis.

Gabriel Henrique Schirmbeck, Marina Seady, Fernanda Telles Fróes, Jéssica Taday, Carollina Da Ré, Jéssica Maria Souza, Carlos Alberto Gonçalves, Marina Concli Leite.

  Dementia is the most prevalent neurodegenerative disorder, characterized by progressive loss of memory and cognitive function. Inflammation is a major aspect in the progression of brain disorders, and inflammatory events have been associated with accelerated deterioration of cognitive function. In the present work, we investigated the impact of low-grade repeated inflammation stimuli induced by lipopolysaccharide (LPS) in hippocampal function and spatial memory. Adult male Wistar rats received a weekly injection of LPS (500 ug/kg) for sixteen weeks, eliciting systemic inflammation. Animals submitted to LPS presented impaired spatial memory and neuroinflammation. While neuronal synaptic markers such as synaptophysin and PSD-95 were unaltered, critical aspects of astrocyte homeostatic functions, such as glutamate uptake and glutathione content, were reduced. Also, glucose uptake and astrocyte lactate transporters were altered, suggesting a disturbance in the astrocyte-neuron coupling. Our present work demonstrates that long-term repeated systemic inflammation can lead to memory impairment and hippocampal metabolic disorders, especially regarding astrocyte function.

Keywords:  Astrocytes; Hippocampus; Lipopolysaccharide; Low-grade repeated inflammation; Memory; Neuroinflammation

DOI:  https://doi.org/10.1016/j.neuro.2023.11.009
Appl Nurs Res. 2023 Dec;pii: S0897-1897(23)00079-4. [Epub ahead of print]74 151745

Ketogenic therapies in Parkinson's disease, Alzheimer's disease, and mild cognitive impairment: An integrative review.

Susan Price, Todd M Ruppar.

  BACKGROUND: Ketogenic therapies have shown benefit for seizure reduction in epilepsy but their impact on other neurologic conditions is less known. In this literature review, the efficacy of ketogenic therapies were assessed in Parkinson's disease (PD), Alzheimer's disease (AD), and mild cognitive impairment (MCI).METHODS: A literature search was conducted using PubMed, Scopus, and Google Scholar focusing on ketogenic therapies in PD, AD, and MCI.
RESULTS: A total of 2565 records were identified with a total of 15 studies (3 for PD and 12 for MCI/AD) meeting criteria for analysis. The ketogenic diet was used in all the PD studies and did show significant improvement in motor function either through vocal quality, gait, freezing, tremor, and/or balance. A variety of ketogenic therapies were utilized in the MCI and AD groups including a ketogenic diet, low-carbohydrate diet, modified Adkins diet, Mediterranean diet with coconut oil supplementation, a ketogenic diet with a ketogenic medium chain triglyceride (kMCT) supplement, as well as ketogenic supplements including a ketogenic drink with kMCT, oral ketogenic compounds (Axona and AC-1202), and MCT oil or emulsion. The ketogenic diet independently showed a non-significant trend towards improvement in cognition. The Mediterranean diet, modified Adkins diet, and low-carbohydrate diet showed statistically significant improvements in some, although not all, of their cognitive measures. Use of ketogenic supplements, drinks, or compounds showed variable results in the AD and MCI groups. The Axona and AC-1202 compounds showed no significant improvement in cognition at the end of their respective 90-day trials. Most MCT supplements did show cognitive improvements, although only after 6 months of adherence. Adherence to the intervention was problematic in most of the diet studies.
CONCLUSION: Ketogenic therapies have promise in PD, AD, and MCI for symptom improvement although larger studies are needed to support their implementation in clinical practice.

Keywords:  Alzheimer's disease; Cognitive dysfunction; Ketogenic diet; Neurodegenerative disorder; Parkinson's disease

DOI:  https://doi.org/10.1016/j.apnr.2023.151745
Magn Reson Med. 2023 Nov 27.

Dynamic T2* relaxometry of hyperpolarized [1-13 C]pyruvate MRI in the human brain and kidneys.

Xiaoxi Liu, Di Cui, Duan Xu, Robert Bok, Zhen J Wang, Daniel B Vigneron, Peder E Z Larson, Jeremy W Gordon.

  PURPOSE: This study aimed to quantify T2*$$ {T}_2^{\ast } $$ for hyperpolarized [1-13 C]pyruvate and metabolites in the healthy human brain and renal cell carcinoma (RCC) patients at 3 T.METHODS: Dynamic T2*$$ {T}_2^{\ast } $$ values were measured with a metabolite-specific multi-echo spiral sequence. The dynamic T2*$$ {T}_2^{\ast } $$ of [1-13 C]pyruvate, [1-13 C]lactate, and 13 C-bicarbonate was estimated in regions of interest in the whole brain, sinus vein, gray matter, and white matter in healthy volunteers, as well as in kidney tumors and the contralateral healthy kidneys in a separate group of RCC patients. T2*$$ {T}_2^{\ast } $$ was fit using a mono-exponential function; and metabolism was quantified using pyruvate-to-lactate conversion rate maps and lactate-to-pyruvate ratio maps, which were compared with and without an estimated T2*$$ {T}_2^{\ast } $$ correction.
RESULTS: The T2*$$ {T}_2^{\ast } $$ of pyruvate was shown to vary during the acquisition, whereas the T2*$$ {T}_2^{\ast } $$ of lactate and bicarbonate were relatively constant through time and across the organs studied. The T2*$$ {T}_2^{\ast } $$ of lactate was similar in gray matter (29.75 ± 1.04 ms), white matter (32.89 ± 0.9 ms), healthy kidney (34.61 ± 4.07 ms), and kidney tumor (33.01 ± 2.31 ms); and the T2*$$ {T}_2^{\ast } $$ of bicarbonate was different between whole-brain (108.17 ± 14.05 ms) and healthy kidney (58.45 ± 6.63 ms). The T2*$$ {T}_2^{\ast } $$ of pyruvate had similar trends in both brain and RCC studies, reducing from 75.56 ± 2.23 ms to 22.24 ± 1.24 ms in the brain and reducing from 122.72 ± 9.86 ms to 57.38 ± 7.65 ms in the kidneys.
CONCLUSION: Multi-echo dynamic imaging can quantify T2*$$ {T}_2^{\ast } $$ and metabolism in a single integrated acquisition. Clear differences were observed in the T2*$$ {T}_2^{\ast } $$ of metabolites and in their behavior throughout the timecourse.

Keywords:  dynamic transverse relaxometry; hyperpolarized 13C; kinetic model; metabolic imaging; multi-echo gradient echo sequence

DOI:  https://doi.org/10.1002/mrm.29942
Alzheimers Dement. 2023 Nov 30.

Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease.

Evgeny J Chumin, Charles P Burton, Rebecca Silvola, Ethan W Miner, Scott C Persohn, Mattia Veronese, Paul R Territo.

  INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage.METHODS: We performed 18 F-FDG positron emission tomography (PET) imaging in 4-, 6-, and 12-month-old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis.
RESULTS: The 5XFAD model mice showed age-related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model.
DISCUSSION: The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.

Keywords:  Alzheimer's disease; connectomics; metabolic covariance networks; preclinical models

DOI:  https://doi.org/10.1002/alz.13538
J Alzheimers Dis Rep. 2023 ;7(1): 1165-1177

Mitochondrial Interaction with Serotonin in Neurobiology and Its Implication in Alzheimer's Disease.

Jing Tian, Eric Du, Lan Guo.

  Alzheimer's disease (AD) is a lethal neurodegenerative disorder characterized by severe brain pathologies and progressive cognitive decline. While the exact cause of this disease remains unknown, emerging evidence suggests that dysregulation of neurotransmitters contributes to the development of AD pathology and symptoms. Serotonin, a critical neurotransmitter in the brain, plays a pivotal role in regulating various brain processes and is implicated in neurological and psychiatric disorders, including AD. Recent studies have shed light on the interplay between mitochondrial function and serotonin regulation in brain physiology. In AD, there is a deficiency of serotonin, along with impairments in mitochondrial function, particularly in serotoninergic neurons. Additionally, altered activity of mitochondrial enzymes, such as monoamine oxidase, may contribute to serotonin dysregulation in AD. Understanding the intricate relationship between mitochondria and serotonin provides valuable insights into the underlying mechanisms of AD and identifies potential therapeutic targets to restore serotonin homeostasis and alleviate AD symptoms. This review summarizes the recent advancements in unraveling the connection between brain mitochondria and serotonin, emphasizing their significance in AD pathogenesis and underscoring the importance of further research in this area. Elucidating the role of mitochondria in serotonin dysfunction will promote the development of therapeutic strategies for the treatment and prevention of this neurodegenerative disorder.

Keywords:  Alzheimer’s disease; mitochondria; neurobiology; pathogenesis; serotonin

DOI:  https://doi.org/10.3233/ADR-230070
Cureus. 2023 Oct;15(10): e48017

Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features.

Rui Diogo, Inês B Rua, Sara Ferreira, Célia Nogueira, Cristina Pereira, Joana Rosmaninho-Salgado, Luísa Diogo.

  Methylmalonyl coenzyme A (CoA) epimerase (MCE) converts D-methylmalonyl-CoA into L-methylmalonyl CoA in the final common degradation pathway of valine, isoleucine, methionine, threonine, odd-chain fatty acids, and cholesterol side chains. Methylmalonyl-CoA epimerase deficiency is an ultra-rare autosomal recessive disorder where methylmalonic acid, methylcitrate, 3-hydroxypropionate, and propionylcarnitine are accumulated. We describe two novel pediatric patients and review the previously reported cases of MCE deficiency. Including our two novel patients, at least 24 cases of MCE deficiency have been described, with a broad clinical spectrum ranging from asymptomatic to severely neurologically impaired patients. Our patients are siblings of Arabic origin who presented with metabolic decompensation with coma and epilepsy during infancy. Methylmalonic aciduria was disclosed, L-methylmalonyl-CoA mutase deficiency was assumed, and they were treated accordingly. When first seen in our country, aged 10 and four years, respectively, both presented severe intellectual disability and spasticity. The younger had an ataxic gait, and the older was wheelchair-ridden. The study of the MMUT, MMAA, MMAB, and MMADHC genes was normal. Subsequently, the pathogenic variant c.139C>T (p.Arg47*) in the MCEE gene was identified in homozygosity in both patients, leading to the diagnosis of MCE deficiency (Online Mendelian Inheritance in Man (OMIM®) 251120, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, MD, USA). Most patients were homozygous for that variant (83% of the alleles). Correct diagnosis allowed treatment adequacy and genetic counseling. Methylmalonyl-CoA epimerase deficiency shares a similar biochemical profile with other rare genetic disorders. Patients present with overlapping clinical features with predominant neurological manifestations; genetic testing is indispensable for diagnosis. We found no association between genotype and biochemical and clinical phenotypes.

Keywords:  intellectual disability; methylmalonic aciduria; methylmalonyl-coa epimerase; seizures; spasticity

DOI:  https://doi.org/10.7759/cureus.48017
Nat Commun. 2023 Nov 29. 14(1): 7824

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.

Philipp Hammerschmidt, Sophie M Steculorum, Cécile L Bandet, Almudena Del Río-Martín, Lukas Steuernagel, Vivien Kohlhaas, Marvin Feldmann, Luis Varela, Adam Majcher, Marta Quatorze Correia, Rhena F U Klar, Corinna A Bauder, Ecem Kaya, Marta Porniece, Nasim Biglari, Anna Sieben, Tamas L Horvath, Thorsten Hornemann, Susanne Brodesser, Jens C Brüning.

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.

DOI: https://doi.org/10.1038/s41467-023-42595-7
Adv Exp Med Biol. 2024 ;1440 73-87

Mass Spectrometry Imaging of Cholesterol and Oxysterols.

William J Griffiths, Eylan Yutuc, Yuqin Wang.

  Mass spectrometry imaging (MSI) is a new technique in the toolbox of the analytical biochemist. It allows the generation of a compound-specific image from a tissue slice where a measure of compound abundance is given pixel by pixel, usually displayed on a color scale. As mass spectra are recorded at each pixel, the data can be interrogated to generate images of multiple different compounds all in the same experiment. Mass spectrometry (MS) requires the ionization of analytes, but cholesterol and other neutral sterols tend to be poorly ionized by the techniques employed in most MSI experiments, so despite their high abundance in mammalian tissues, cholesterol is poorly represented in the MSI literature. In this chapter, we discuss some of the MSI studies where cholesterol has been imaged and introduce newer methods for its analysis by MSI. Disturbed cholesterol metabolism is linked to many disorders, and the potential of MSI to study cholesterol, its precursors, and its metabolites in animal models and from human biopsies will be discussed.

Keywords:  24S-hydroxycholesterol; Cholesterol; Mass spectrometry; Mass spectrometry imaging; Neurodegeneration; Oxysterol

DOI:  https://doi.org/10.1007/978-3-031-43883-7_5
J Neurol. 2023 Nov 27.

AMPK role in epilepsy: a promising therapeutic target?

Yingbei Qi, Yong-Mei Zhang, Ya-Nan Gao, Wen-Gang Chen, Ting Zhou, Liuliu Chang, Yi Zang, Jia Li.

  Epilepsy is a complex and multifaceted neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to its diverse etiology and often-refractory nature. This comprehensive review highlights the pivotal role of AMP-activated protein kinase (AMPK), a key metabolic regulator involved in cellular energy homeostasis, which may be a promising therapeutic target for epilepsy. Current therapeutic strategies such as antiseizure medication (ASMs) can alleviate seizures (up to 70%). However, 30% of epileptic patients may develop refractory epilepsy. Due to the complicated nature of refractory epilepsy, other treatment options such as ketogenic dieting, adjunctive therapy, and in limited cases, surgical interventions are employed. These therapy options are only suitable for a select group of patients and have limitations of their own. Current treatment options for epilepsy need to be improved. Emerging evidence underscores a potential association between impaired AMPK functionality in the brain and the onset of epilepsy, prompting an in-depth examination of AMPK's influence on neural excitability and ion channel regulation, both critical factors implicated in epileptic seizures. AMPK activation through agents such as metformin has shown promising antiepileptic effects in various preclinical and clinical settings. These effects are primarily mediated through the inhibition of the mTOR signaling pathway, activation of the AMPK-PI3K-c-Jun pathway, and stimulation of the PGC-1α pathway. Despite the potential of AMPK-targeted therapies, several aspects warrant further exploration, including the detailed mechanisms of AMPK's role in different brain regions, the impact of AMPK under various conditional circumstances such as neural injury and zinc toxicity, the long-term safety and efficacy of chronic metformin use in epilepsy treatment, and the potential benefits of combination therapy involving AMPK activators. Moreover, the efficacy of AMPK activators in refractory epilepsy remains an open question. This review sets the stage for further research with the aim of enhancing our understanding of the role of AMPK in epilepsy, potentially leading to the development of more effective, AMPK-targeted therapeutic strategies for this challenging and debilitating disorder.

Keywords:  AMPK; Epilepsy; Ion Channels; Metabolism; Neuron Modulation; mTOR

DOI:  https://doi.org/10.1007/s00415-023-12062-w
ACS Omega. 2023 Nov 14. 8(45): 43118-43129

Allyl Isothiocyanate Maintains DHA-Containing Glycerophospholipids and Ameliorates the Cognitive Function Decline in OVX Mice.

Akika Nagata, Shiori Oishi, Nanako Kirishita, Keita Onoda, Takuma Kobayashi, Yuko Terada, Akira Minami, Nanami Senoo, Yasukiyo Yoshioka, Kunitoshi Uchida, Keisuke Ito, Shinji Miura, Noriyuki Miyoshi.

Low-temperature-induced fatty acid desaturation is highly conserved in animals, plants, and bacteria. Allyl isothiocyanate (AITC) is an agonist of the transient receptor potential ankyrin 1 (TRPA1), which is activated by various chemophysiological stimuli, including low temperature. However, whether AITC induces fatty acid desaturation remains unknown. We showed here that AITC increased levels of glycerophospholipids (GP) esterified with unsaturated fatty acids, especially docosahexaenoic acid (DHA) in TRPA1-expressing HEK cells. Additionally, GP-DHA including phosphatidylcholine (18:0/22:6) and phosphatidylethanolamine (18:0/22:6) was increased in the brain and liver of AITC-administered mice. Moreover, intragastrical injection of AITC in ovariectomized (OVX) female C57BL/6J mice dose-dependently shortened the Δlatency time determined by the Morris water maze test, indicating AITC ameliorated the cognitive function decline in these mice. Thus, the oral administration of AITC maintains GP-DHA in the liver and brain, proving to be a potential strategy for preventing cognitive decline.

DOI: https://doi.org/10.1021/acsomega.3c06622
Cell Rep. 2023 Nov 30. pii: S2211-1247(23)01478-X. [Epub ahead of print]42(12): 113466

NGLY1 mutations cause protein aggregation in human neurons.

Andreea Manole, Thomas Wong, Amanda Rhee, Sammy Novak, Shao-Ming Chin, Katya Tsimring, Andres Paucar, April Williams, Traci Fang Newmeyer, Simon T Schafer, Idan Rosh, Susmita Kaushik, Rene Hoffman, Songjie Chen, Guangwen Wang, Michael Snyder, Ana Maria Cuervo, Leo Andrade, Uri Manor, Kevin Lee, Jeffrey R Jones, Shani Stern, Maria C Marchetto, Fred H Gage.

  Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1's activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.

Keywords:  CP: Neuroscience; NGLY1 deficiency; chaperones; fragmented mitochondria; neural cells; organoids; protein aggregates

DOI:  https://doi.org/10.1016/j.celrep.2023.113466
PLoS One. 2023 ;18(11): e0294312

Trehalose enhances mitochondria deficits in human NPC1 mutant fibroblasts but disrupts mouse Purkinje cell dendritic growth ex vivo.

Collin M MacLeod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto.

Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We found that in NPC1 mutant fibroblasts, serum starvation or/and trehalose treatment, both activators of TFEB, reversed mitochondria fragmentation to a more tubular mitochondrion. Trehalose treatment also decreased the accumulation of Filipin+ cholesterol in NPC1 mutant fibroblasts. However, trehalose treatment in cerebellar organotypic slices (COSCs) from wild-type and Npc1nmf164 mice caused mitochondria fragmentation and lack of dendritic growth and degeneration in developmental Purkinje cells. Our data suggest, that although trehalose successfully restores mitochondria length and decreases cholesterol accumulation in NPC1 mutant fibroblasts, in COSCs, Purkinje cells mitochondria and dendritic growth are negatively affected possibly through the overactivation of the TFEB-lysosomal-autophagy pathway.

DOI: https://doi.org/10.1371/journal.pone.0294312
Food Chem. 2023 Nov 23. pii: S0308-8146(23)02674-2. [Epub ahead of print]439 138056

Effect of consumption of sheep and cow milk on rat brain fatty acid and phospholipid composition.

Yutong Gao, Alan Carne, Wayne Young, Keegan Burrow, Samer Naji, Sara J Fraser-Miller, Keith C Gordon, Alaa El-Din A Bekhit.

  The effect of sheep milk and cow milk on the lipid composition of rat brain was investigated in two feeding experiments of 28-days duration. Total lipids of the rat brain were extracted using ethanol-hexane, and the fatty acids and phospholipid contents analysed using gas chromatography with flame ionization detection (GC-FID) and phosphorus-31 nuclear magnetic resonance (31P NMR). Furthermore, freeze-dried pooled samples were analysed using attenuated total reflectance Fourier Transform Infrared and Fourier Transform Raman Spectroscopy and analysed with multivariate methods. A significantly (P < 0.05) higher C18:2 content was found in the cow milk group compared with sheep milk-treated groups in Study one. In Study two, a significantly (P < 0.05) lower C16:0 content was present in the sheep milk-treated group compared to the control low Ca/P group. No significant (P > 0.05) differences were observed in the spectroscopy analyses. It is concluded that sheep and cow milks fed to rats for 28-days had a low effect on the brain lipidome.

Keywords:  Cow milk; FTIR; Fatty acids; Fourier Transform Raman Spectroscopy; Phospholipids; Sheep milk

DOI:  https://doi.org/10.1016/j.foodchem.2023.138056
Brain Spine. 2023 ;3 102686

Quantification of pyruvate in-vitro using mid-infrared spectroscopy: Developing a system for microdialysis monitoring in traumatic brain injury patients.

Chisomo Zimphango, Farah C Alimagham, Tanya Hutter, Peter J Hutchinson, Keri L H Carpenter.

  Introduction: Complex metabolic disruption is a major aspect of the pathophysiology of traumatic brain injury (TBI). Pyruvate is an intermediate in glucose metabolism and considered one of the most clinically informative metabolites during neurocritical care of TBI patients, especially in deducing the lactate/pyruvate ratio (LPR) - a widely-used metric for probing the brain's metabolic redox state. LPR is conventionally measured offline on a bedside analyzer, on hourly accumulations of brain microdialysate. However, there is increasing interest within the field to quantify microdialysate pyruvate and LPR continuously in near-real-time within its pathophysiological range. We have previously measured pure standard pyruvate in-vitro using mid-infrared transmission, employing a commercially available external cavity-quantum cascade laser (EC-QCL) and a microfluidic flow cell and reported a limit of detection (LOD) of 0.1 mM.Research question: The present study was to test whether the current commercially available state-of-the-art mid-infrared transmission system, can detect pyruvate levels lower than previously reported.
Materials and methods: We measured pyruvate in perfusion fluid on the mid-infrared transmission system also equipped with an EC-QCL and microfluidic flow cells, tested at three pathlengths.
Results: We characterised the system to extract its relevant figures-of-merit and report the LOD of 0.07 mM.
Discussion and conclusion: The reported LOD of 0.07 mM represents a clinically recognised threshold and is the lowest value reported in the field for a sensor that can be coupled to microdialysis. While work is ongoing for a definitive evaluation of the system to measuring pyruvate, these preliminary results set a good benchmark and reference against which future developments can be examined.

Keywords:  Cerebral metabolism; Cerebral microdialysis; Mid-infrared spectroscopy; Pyruvate; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.bas.2023.102686
Brain Res. 2023 Nov 27. pii: S0006-8993(23)00461-4. [Epub ahead of print] 148690

A Gad2 specific Slc6a8 deletion recapitulates the contextual and cued freezing deficits seen in Slc6a8-/y mice.

Chiho Sugimoto, Marla K Perna, Samantha L Regan, Erin A Tepe, Rosalyn Liou, Adam L Fritz, Michael T Williams, Charles V Vorhees, Matthew R Skelton.

  The creatine (Cr)-phosphocreatine shuttle is essential for ATP homeostasis. In humans, the absence of brain Cr causes significant intellectual disability, epilepsy, and language delay. Mutations of the creatine transporter (SLC6A8) are the most common cause of Cr deficiency. In rodents, Slc6a8 deletion causes deficits in spatial learning, novel object recognition (NOR), as well as in contextual and cued freezing. The mechanisms that underlie these cognitive deficits are not known. Due to the heterogeneous nature of the brain, it is important to determine which systems are affected by a loss of Cr. In this study, we generated mice lacking Slc6a8 in GABAergic neurons by crossing Slc6a8FL mice with Gad2-Cre mice. These Gad2-specific Slc6a8 knockout (cKO) mice, along with the ubiquitous Slc6a8 KO (Slc6a8-/y), Gad2-Cre+, and wild-type (WT) mice were tested in the Morris water maze, NOR, conditioned freezing, and the radial water maze. Similar to the Slc6a8-/y mice, cKO mice had reduced contextual and cued freezing compared with WT mice. The cKO mice had a mild spatial learning deficit during the reversal phase of the MWM, however they were not as pronounced as in Slc6a8-/y mice. In NOR, the Gad2-Cre mice spent less time with the novel object, similar to the reduced novel time in the cKO mice. There were no changes in radial water maze performance. Slc6a8 deletion in GABAergic neurons is sufficient to recapitulate the conditioned freezing deficits seen in Slc6a8-/y mice.

Keywords:  Conditioned fear; Creatine; Creatine transporter; GABA; Learning; Memory

DOI:  https://doi.org/10.1016/j.brainres.2023.148690
Glia. 2023 Nov 27.

Clearance of β-amyloid mediated by autophagy is enhanced by MTORC1 inhibition but not AMPK activation in APP/PSEN1 astrocytes.

Marta García-Juan, Lara Ordóñez-Gutiérrez, Francisco Wandosell.

  Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism-catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.

Keywords:  AICAR; Alzheimer; amyloid accumulation; autophagy; cultured astrocytes; metformin; rapamycin

DOI:  https://doi.org/10.1002/glia.24492
Glycobiology. 2023 Nov 28. pii: cwad095. [Epub ahead of print]

Knockout of the intellectual disability-linked gene Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory.

Sohyun Moon, Hiu Ham Lee, Stephanie Archer-Hartmann, Naoko Nagai, Zainab Mubasher, Mahima Parappurath, Laiba Ahmed, Raddy L Ramos, Koji Kimata, Parastoo Azadi, Weikang Cai, Jerry Yingtao Zhao.

  Heparan sulfate (HS) is a linear polysaccharide that plays a key role in cellular signaling networks. HS functions are regulated by its 6-O-sulfation, which is catalyzed by three HS 6-O-sulfotransferases (HS6STs). Notably, HS6ST2 is mainly expressed in the brain and HS6ST2 mutations are linked to brain disorders, but the underlying mechanisms remain poorly understood. To determine the role of Hs6st2 in the brain, we carried out a series of molecular and behavioral assessments on Hs6st2 knockout mice. We first carried out strong anion exchange-high performance liquid chromatography and found that knockout of Hs6st2 moderately decreases HS 6-O-sulfation levels in the brain. We then assessed body weights and found that Hs6st2 knockout mice exhibit increased body weight, which is associated with abnormal metabolic pathways. We also performed behavioral tests and found that Hs6st2 knockout mice showed memory deficits, which recapitulate patient clinical symptoms. To determine the molecular mechanisms underlying the memory deficits, we used RNA sequencing to examine transcriptomes in two memory-related brain regions, the hippocampus and cerebral cortex. We found that knockout of Hs6st2 impairs transcriptome in the hippocampus, but only mildly in the cerebral cortex. Furthermore, the transcriptome changes in the hippocampus are enriched in dendrite and synapse pathways. We also found that knockout of Hs6st2 decreases HS levels and impairs dendritic spines in hippocampal CA1 pyramidal neurons. Taken together, our study provides novel molecular and behavioral insights into the role of Hs6st2 in the brain, which facilitates a better understanding of HS6ST2 and HS-linked brain disorders.

Keywords:  Dendritic spine; HS6ST2; heparan sulfate; heparan sulfate 6-O-sulfation; memory

DOI:  https://doi.org/10.1093/glycob/cwad095