bims-medebr 2024-11-03 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒11‒03
seven papers selected by
Regina F. Fernández, Johns Hopkins University

In the Brain, It Is Not All about Sugar.
Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Myelin Debris-Treated Microglial Cell Lines Activates the Gene Expression of Cholesterol Efflux Transporter ABCA1.
Inhibiting the cholesterol storage enzyme ACAT1/SOAT1 in aging Apolipoprotein E4 mice alter their brains inflammatory profiles.
Neurometabolic substrate transport across brain barriers in diabetes mellitus: Implications for cognitive function and neurovascular health.
Transcriptomic and metabolic signatures of neural cells cultured under a physiological-like environment.
Monitoring Myelin Lipid Composition and the Structure of Myelinated Fibers Reveals a Maturation Delay in CMT1A.
miR-124 coordinates metabolic regulators acting at early stages of human neurogenesis.

NeuroSci. 2024 Jun;5(2): 209-221

In the Brain, It Is Not All about Sugar.

Bernardo C Antunes, Tomás Mateus, Vanessa A Morais.

  The maintenance of energetic homeostasis relies on a tight balance between glycolysis and mitochondrial oxidative phosphorylation. The case of the brain is a peculiar one, as although entailing a constant demand for energy, it is believed to rely mostly on glucose, particularly at the level of neurons. Nonetheless, this has been challenged by studies that show that alternatives such as lactate, ketone bodies, and glutamate can be used as fuels to sustain neuronal activity. The importance of fatty acid (FA) metabolism to this extent is still unclear, albeit sustaining a significant energetic output when compared to glucose. While several authors postulate a possible role of FA for the energetic homeostasis of the brain, several others point out the intrinsic features of this pathway that make its contribution difficult to explain in the context of neuronal bioenergetics. Moreover, fueling preference at the synapse level is yet to be uncovered. In this review, we discuss in detail the arguments for and against the brain usage of FA. Furthermore, we postulate that the importance of this fuel may be greater at the synapse, where local mitochondria possess a set of features that enable a more effective usage of this fuel source.

Keywords:  brain; fatty acid metabolism; mitochondria; synapse

DOI:  https://doi.org/10.3390/neurosci5020016
Biomolecules. 2024 Oct 14. pii: 1301. [Epub ahead of print]14(10):

Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Myelin Debris-Treated Microglial Cell Lines Activates the Gene Expression of Cholesterol Efflux Transporter ABCA1.

Thao N Huynh, Matthew C Havrda, George J Zanazzi, Catherine C Y Chang, Ta Yuan Chang.

  Aging is the major risk factor for Alzheimer's disease (AD). In the aged brain, myelin debris accumulates and is cleared by microglia. Phagocytosed myelin debris increases neutral lipid droplet content in microglia. Neutral lipids include cholesteryl esters (CE) and triacylglycerol (TAG). To examine the effects of myelin debris on neutral lipid content in microglia, we added myelin debris to human HMC3 and mouse N9 cells. The results obtained when using 3H-oleate as a precursor in intact cells reveal that myelin debris significantly increases the biosynthesis of CE but not TAG. Mass analyses have shown that myelin debris increases both CE and TAG. The increase in CE biosynthesis was abolished using inhibitors of the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1). ACAT1 inhibitors are promising drug candidates for AD treatment. In myelin debris-loaded microglia, treatment with two different ACAT1 inhibitors, K604 and F12511, increased the mRNA and protein content of ATP-binding cassette subfamily A1 (ABCA1), a protein that is located at the plasma membrane and which controls cellular cholesterol disposal. The effect of the ACAT1 inhibitor on ABCA1 was abolished by preincubating cells with the liver X receptor (LXR) antagonist GSK2033. We conclude that ACAT1 inhibitors prevent the accumulation of cholesterol and CE in myelin debris-treated microglia by activating ABCA1 gene expression via the LXR pathway.

Keywords:  ACAT inhibitor; ATP-binding cassette subfamily A member 1; Alzheimer’s disease; acyl-CoA:cholesterol acyltransferase; aging; cholesterol; cholesteryl esters; foam cell; liver X receptor; microglia; myelin debris; sterol O-acyltransferase

DOI:  https://doi.org/10.3390/biom14101301
bioRxiv. 2024 Oct 25. pii: 2024.10.24.620063. [Epub ahead of print]

Inhibiting the cholesterol storage enzyme ACAT1/SOAT1 in aging Apolipoprotein E4 mice alter their brains inflammatory profiles.

Thao N Huynh, Emma N Fikse, Matthew C Havrda, Catherine C Y Chang, Ta Yuan Chang.

Aging and Apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer's disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4 dependent phenotypes. Toll-like receptor 4 (TLR4) is a key player in inflammation, its regulation is associated with cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. In this study, we found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activated ABCA1, and dampened LPS dependent NFkB activation. In vivo, a two-week injections of nanoparticle F12511, which consists of DSPE-PEG 2000 , phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines including IL-1β in APOE4 mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.

DOI: https://doi.org/10.1101/2024.10.24.620063
Neurosci Lett. 2024 Oct 24. pii: S0304-3940(24)00407-5. [Epub ahead of print]843 138028

Neurometabolic substrate transport across brain barriers in diabetes mellitus: Implications for cognitive function and neurovascular health.

Ritwick Mondal, Shramana Deb, Dipanjan Chowdhury, Shramana Sarkar, Aakash Guha Roy, Gourav Shome, Vramanti Sarkar, Durjoy Lahiri, Julián Benito-León.

  Neurometabolic homeostasis in the brain depends on the coordinated transport of glucose and other essential substrates across brain barriers, primarily the blood-brain barrier and the blood-cerebrospinal fluid barrier. In type 2 diabetes mellitus (T2DM), persistent hyperglycemia disrupts these processes, leading to neurovascular dysfunction and cognitive impairment. This review examines how T2DM alters glucose and neurometabolite transport, emphasizing the role of glucose transporters and the astrocyte-neuron lactate shuttle in maintaining cerebral energy balance. Reduced expression of glucose transporters and impaired neurovascular coupling are key contributors to cognitive decline in T2DM. Additionally, the review highlights insulin's pivotal role in the hippocampus, where it enhances neuro-glial coupling and modulates astrocyte glucose uptake to support neuronal energy demands. Synthesizing current findings, we underscore the importance of therapeutic strategies aimed at correcting glucose transport dysregulation to alleviate diabetes-associated cognitive decline.

Keywords:  Blood-Brain Barrier; Cognitive Decline; Glucose Transporters; Lactate Transport; Neurodegeneration; Neurovascular Coupling; Type 2 Diabetes Mellitus

DOI:  https://doi.org/10.1016/j.neulet.2024.138028
J Biol Chem. 2024 Oct 28. pii: S0021-9258(24)02439-6. [Epub ahead of print] 107937

Transcriptomic and metabolic signatures of neural cells cultured under a physiological-like environment.

Emilio Fernandez, Moussa Warde, Israel Manjarres-Raza, Veronica Bobo-Jimenez, Maria Martinez-Luna, Carlos Vicente-Gutierrez, Dario Garcia-Rodriguez, Daniel Jimenez-Blasco, Angeles Almeida, Juan P Bolaños.

  Cultured brain cells are used conventionally to investigate fundamental neurobiology and identify therapeutic targets against neural diseases. However, standard culture conditions do not simulate the natural cell microenvironment, thus hampering in vivo translational insight. Major weaknesses include atmospheric (21%) O2 tension and lack of intercellular communication, two factors likely impacting metabolism and signaling. Here, we addressed this issue in mouse neurons and astrocytes in primary culture. We found that the signs of cellular and mitochondrial integrity were optimal when these cells were acclimated to grow in co-culture, to emulate intercellular coupling, under physiological (5%) O2 tension. Transcriptomic scrutiny, performed to elucidate the adaptive mechanism involved, revealed that the vast majority of differentially expressed transcripts were downregulated in both astrocytes and neurons. Gene ontology evaluation unveiled that the largest group of altered transcripts was glycolysis, which was experimentally validated by metabolic flux analyses. This protocol and database resource for neural cells grown under in vivo-like microenvironment may move forward the translation of basic into applied neurobiological research.

Keywords:  Astrocyte; energy metabolism; glycolysis; hypoxia; neuron; transcriptomics

DOI:  https://doi.org/10.1016/j.jbc.2024.107937
Int J Mol Sci. 2024 Oct 19. pii: 11244. [Epub ahead of print]25(20):

Monitoring Myelin Lipid Composition and the Structure of Myelinated Fibers Reveals a Maturation Delay in CMT1A.

Giovanna Capodivento, Mattia Camera, Nara Liessi, Anna Trada, Doriana Debellis, Angelo Schenone, Andrea Armirotti, Davide Visigalli, Lucilla Nobbio.

  Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by a deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130,000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A.

Keywords:  CMT1A; axonal growth; myelin lipids; myelin maturation; nervous system development; sphingolipids

DOI:  https://doi.org/10.3390/ijms252011244
Commun Biol. 2024 Oct 25. 7(1): 1393

miR-124 coordinates metabolic regulators acting at early stages of human neurogenesis.

Geurim Son, Yongwoo Na, Yongsung Kim, Ji-Hoon Son, Gregory D Clemenson, Simon T Schafer, Jong-Yeon Yoo, Sarah L Parylak, Apua Paquola, Hyunsu Do, Dayeon Kim, Insook Ahn, Mingyu Ju, Chanhee S Kang, Younghee Ju, Eunji Jung, Aidan H McDonald, Youngjin Park, Gilhyun Kim, Se-Bum Paik, Junho Hur, Joon Kim, Yong-Mahn Han, Seung-Hee Lee, Fred H Gage, Jong-Seo Kim, Jinju Han.

Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions.

DOI: https://doi.org/10.1038/s42003-024-07089-2