Glucose-1,6-bisphosphate: A new gatekeeper of cerebral mitochondrial pyruvate uptake DOI Creative Commons
Motahareh Solina Safari,

Priska Woerl,

Carolin Garmsiri

и другие.

Molecular Metabolism, Год журнала: 2024, Номер 88, С. 102018 - 102018

Опубликована: Авг. 24, 2024

Glucose-1,6-bisphosphate (G-1,6-BP), a byproduct of glycolysis that is synthesized by phosphoglucomutase 2 like 1 (PGM2L1), particularly abundant in neurons. G-1,6-BP sensitive to the glycolytic flux, due its dependence on 1,3-bisphosphoglycerate as phosphate donor, and energy state, degradation inosine monophosphate-activated phosphomannomutase 1. Since exact role this metabolite remains unclear, our aim was elucidate specific function brain. The effect PGM2L1 neuronal post-ischemic viability assessed siRNA-mediated knockdown primary mouse Acute brain slices were used correlate reduction upon ischemia changes carbon metabolism 13C6-glucose tracing. A drug affinity responsive target stability assay test if interacts with mitochondrial pyruvate carrier (MPC) subunits protein extracts. Human embryonic kidney cells expressing MPC bioluminescence resonance transfer sensor analyze how overexpression affects activity. uptake oxygen consumption rates analyzed isolated mitochondria. predicted upstream kinase overexpressed human neuroblastoma cell line levels measured. We found quickly degraded reperfusion. Knockdown neurons reduced viability, indicating plays neuroprotective role. not accompanied alterations but we did see incorporation into citrate, suggesting potential or metabolism. Indeed, interacted both increased G-1,6-BP, at concentrations brain, enhanced pyruvate-induced rates. Overexpression inhibited activity, showing besides metabolism, also signaling pathways can regulate levels. provide evidence positively regulates viability. These compelling data reveal novel mechanism which couple glycolysis-derived tricarboxylic acid cycle. This process cell's energetic cascades, offering many regulatory means fine-tune critical metabolic step.

Язык: Английский

Customized Intranasal Hydrogel Delivering Methylene Blue Ameliorates Cognitive Dysfunction against Alzheimer's Disease DOI
Yujing Liu, Yun Tan,

Guopan Cheng

и другие.

Advanced Materials, Год журнала: 2024, Номер 36(19)

Опубликована: Фев. 23, 2024

Abstract The accumulation of hyperphosphorylated tau protein aggregates is a key pathogenic event in Alzheimer's disease (AD) and induces mitochondrial dysfunction reactive oxygen species overproduction. However, the treatment AD remains challenging owning to hindrance caused by blood–brain barrier (BBB) complex pathology AD. Nasal delivery represents an effective means circumventing BBB delivering drugs brain. In this study, black phosphorus (BP) used as drug carrier, well antioxidant, loaded with aggregation inhibitor, methylene blue (MB), obtain BP‐MB. For intranasal (IN) delivery, thermosensitive hydrogel fabricated cross‐linking carboxymethyl chitosan aldehyde Pluronic F127 (F127‐CHO) micelles. BP‐MB nanocomposite incorporated into BP‐MB@Gel. BP‐MB@Gel could be injected intranasally, providing high nasal mucosal retention controlled release. After IN administration, continuously released delivered brain, exerting synergistic therapeutic effects suppressing neuropathology, restoring function, alleviating neuroinflammation, thus inducing cognitive improvements mouse models These findings highlight potential strategy for brain‐targeted management pathologies

Язык: Английский

Процитировано

36
Exploring the causal relationships between type 2 diabetes and neurological disorders using a Mendelian randomization strategy DOI Creative Commons

Yongfang Wei,

Shuling Xu,

Zhaoquan Wu

и другие.

Medicine, Год журнала: 2024, Номер 103(46), С. e40412 - e40412

Опубликована: Ноя. 15, 2024

While there is ample evidence indicating an increased occurrence of general neurological conditions among individuals with diabetes, has been limited exploration into the cause-and-effect connection between type 2 diabetes (T2D) and specific disorders, including like carpal tunnel syndrome Bell’s palsy. We used Mendelian randomization (MR) approach to investigate causal effects T2D on 67 diseases. primarily utilized inverse-variance weighted method for analysis, also employed median MR-Egger methods in our study. To detect correct potential outliers, MR-PRESSO analysis was used. Heterogeneity assessed using Cochrane Q-values. The MR analyses found a possible relationship risk increase 8 diseases at suggestive level ( P < .05). Notably, positive findings that met false discovery rate threshold, nerve, nerve root, plexus disorders (odds ratio [OR] = 1.11; 95% confidence interval [CI] 1.08–1.15); (OR 1.05; CI 1.03–1.07) 1.10; 1.05–1.16) were identified. Our affirm association certain disorders.

Язык: Английский

Процитировано

33
Tirzepatide prevents neurodegeneration through multiple molecular pathways DOI Creative Commons

Rosaria Anna Fontanella,

Puja Ghosh,

Ada Pesapane

и другие.

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 29, 2024

Abstract Background Several evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated molecular processes underlying protective effect Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide agonist (GIP-RA)/ GLP-1RA, against learning memory disorders. Methods We investigated effects TIR on markers neuronal growth (CREB BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, AGBL4), insulin resistance (GLUT1, GLUT4, GLUT3 SORBS1) neuroblastoma cell line (SHSY5Y) exposed to normal high glucose concentration. The potential role DNA methylation genes involved neuroprotection epigenetic modulators (miRNA 34a), 212), 29c) was also investigated. proliferation detected measuring Ki-67 through flow cytometry. data were analysed SPSS IBM Version 23 or GraphPad Prism 7.0 software expressed as means ± SEM. Differences between mean values considered significant at p-value < 0.05. used for drawing figures. Results For first time, it highlighted: (a) activation pAkt/CREB/BDNF pathway downstream signaling cascade; (b) efficacy neuroprotection; (c) counteracting hyperglycemia resistance-related level. Conclusions can ameliorate glucose-induced neurodegeneration overcome resistance. Thus, study provides new insight into diabetes-related neuropathy. Graphical

Язык: Английский

Процитировано

21
Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation DOI Creative Commons
Xiao‐Yi Xiong,

Xinru Pan,

Xia-Xia Luo

и другие.

Theranostics, Год журнала: 2024, Номер 14(11), С. 4297 - 4317

Опубликована: Янв. 1, 2024

Aim:Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether role accumulated ischemia phase is neuroprotection or not remains largely unknown.Thus, in this study, we aimed investigate roles and mechanisms brain regulating injury stroke.Methods Results: Pharmacological inhibition production by either inhibiting LDHA glycolysis markedly attenuated mouse stroke.In contrast, additional supplement further aggravates injury, which may be closely related induction neuronal death A1 astrocytes.The contributing increased promotive formation protein lysine lactylation (Kla), while post-treatment did influence Kla levels with neuroprotection.Increased were found mainly neurons HPLC-MS/MS analysis immunofluorescent staining.Then, pharmacological blocking shuttle showed decreased brains.Additionally, Ldha specific knockout astrocytes (Aldh1l1 CreERT2 ; fl/fl mice, cKO) mice MCAO constructed results that level was accompanied a decrease volume cerebral infarction cKO compared control groups.Furthermore, writer p300 its antagonist A-485 significantly alleviates glial activation reduction level, resulting extending window improving functional recovery for stroke.Conclusion: Collectively, derived from promoting formation, suggesting presents new therapeutic targets treatment stroke.

Язык: Английский

Процитировано

21
Local and dynamic regulation of neuronal glycolysis in vivo DOI Creative Commons
Aaron Wolfe, John N. Koberstein, Chadwick B. Smith

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(3)

Опубликована: Янв. 10, 2024

Energy metabolism supports neuronal function. While it is well established that changes in energy underpin brain plasticity and function, less known about how individual neurons modulate their metabolic states to meet varying demands. This because most approaches used examine living organisms lack the resolution visualize within circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, use

Язык: Английский

Процитировано

13
Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation DOI Creative Commons
Kuldeep Tripathi, Dorit Ben‐Shachar

Cells, Год журнала: 2024, Номер 13(5), С. 410 - 410

Опубликована: Фев. 27, 2024

Mitochondria, the energy suppliers of cells, play a central role in variety cellular processes essential for survival or leading to cell death. Consequently, mitochondrial dysfunction is implicated numerous general and CNS disorders. The clinical manifestations include metabolic disorders, immune system, tumorigenesis, neuronal behavioral abnormalities. In this review, we focus on CNS, which has unique characteristics therefore highly dependent mitochondria. First, review mitochondria development, synaptogenesis, plasticity, behavior as well their adaptation intricate connections between different types brain. Then, sparse knowledge mechanisms exogenous uptake describe attempts determine half-life transplantation long-term effects sprouting, proteome, behavior. We further discuss potential serve tool study causal link activity Next, transplantation’s therapeutic various Finally, basic reverse—translation challenges approach that currently hinder use transplantation.

Язык: Английский

Процитировано

12
Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency DOI
Haoming Wang, John Vant, Andrew Zhang

и другие.

Nature Metabolism, Год журнала: 2024, Номер 6(9), С. 1712 - 1735

Опубликована: Сен. 11, 2024

Язык: Английский

Процитировано

12
NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport DOI Creative Commons
Sen Yang, Zhen-Xian Niou,

Andrea Enriquez

и другие.

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 29, 2024

Abstract Background Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by mononucleotide adenylyl transferase 2 (NMNAT2) CNS neurons. NMNAT2 mRNA levels reduced brains Alzheimer’s, Parkinson’s, Huntington’s disease. Here we addressed whether required axonal health cortical glutamatergic neurons, whose long-projecting axons vulnerable neurodegenerative conditions. We also tested if maintains ensuring ATP transport, critical function. Methods generated mouse cultured neuron models to determine impact loss from neurons on energetic morphological integrity. In addition, determined exogenous NAD supplementation or inhibiting a hydrolase, sterile alpha TIR motif-containing protein 1 (SARM1), prevented deficits caused loss. This study used combination techniques, including genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, anti-sense oligos. Results provide vivo evidence that survival. Using vitro studies, demonstrate NAD-redox potential “on-board” via glycolysis vesicular cargos distal axons. Exogenous + KO restores resumes fast transport. Finally, both reducing activity SARM1, degradation enzyme, can reduce transport suppress axon degeneration Conclusion ensures maintaining redox ensure efficient

Язык: Английский

Процитировано

10
Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation DOI Creative Commons
Bruno Chausse,

Nikolai Malorny,

Andrea Lewen

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июнь 22, 2024

Abstract Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant brain, where metabolism must precisely regulated to maintain appropriate neuronal excitability synaptic transmission. Direct evidence that microglia impact on has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings mathematical modeling, we investigated microglia-mediated disturbances brain energetics during neuroinflammation. Our results suggest proinflammatory showing enhanced nitric oxide release decreased CX3CR1 expression transiently increase lactate/glucose ratio depends transcriptional microglia, not neurons. In this condition, network activity such as gamma oscillations (30–70 Hz) fueled increased ATP production mitochondria, is reflected elevated consumption. During dysregulated inflammation, high demand low glucose boundary conditions for fitness revealed kinetic modeling single neuron energetics. Collectively, these findings indicate flexibility protects function against alterations local moderate

Язык: Английский

Процитировано

10
Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia DOI Open Access
Caio Yogi Yonamine, Maria Luiza Estimo Michalani, Rafael Junges Moreira

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(22), С. 16480 - 16480

Опубликована: Ноя. 18, 2023

The association of diabetes with cognitive dysfunction has at least 60 years history, which started the observation that children type 1 mellitus (T1D), who had recurrent episodes hypoglycemia and consequently low glucose supply to brain, showed a deficit capacity. Later, growing incidence 2 (T2D) dementia in aged populations revealed their high association, reduced neuronal also been considered as key mechanism, despite hyperglycemia. Here, we discuss role functioning/preservation, how peripheral blood accesses intracellular compartment, including exquisite flux across blood–brain barrier (BBB) complex network transporters, dementia-related areas such hippocampus. In addition, insulin resistance-induced abnormalities hippocampus obese/T2D patients, inflammatory stress, oxidative mitochondrial increased generation advanced glycated end products BBB dysfunction, well dementia/Alzheimer’s disease, are addressed. Finally, these accompained by reduction expression translocation capacity insulin-sensitive transporter GLUT4 hippocampal neurons, leads neurocytoglycopenia eventually dysfunction. This knowledge should further encourage investigations into beneficial effects promising therapeutic approaches could improve central sensitivity expression, fight diabetes-related dysfunctions.

Язык: Английский

Процитировано

19