bims-medebr 2023-07-16 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–07–16
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Cholesterol Metabolism in Aging and Age-Related Disorders.
Ketone bodies supplementation restores the barrier function, induces a metabolic switch, and elicits beta-hydroxybutyrate diffusion across a monolayer of iPSC-derived brain microvascular endothelial cells.
The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.
Longitudinal assessment of mitochondrial dysfunction in acute traumatic brain injury using hyperpolarized [1-13 C]pyruvate.
The presence of pyruvate carboxylase in the human brain and its role in the survival of cultured human astrocytes.
Developmental brain lipidomics is influenced by postnatal chlorpyrifos exposure and APOE genetic background in mice.
Establishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system.
N-Acetyl Serotonin Provides Neuroprotective Effects by Inhibiting Ferroptosis in the Neonatal Rat Hippocampus Following Hypoxic Brain Injury.
Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.
Lipid peroxidation and neuroinflammation: A possible link between maternal fructose intake and delay of acquisition of neonatal reflexes in Wistar female rats.
Abnormal cerebral metabolism and metabolic connectivity in individuals with heroin dependence: an integrated resting-state PET/fMRI study in large-scale networks.
Adult-Onset CNS Sulfatide Deficiency Causes Sex-Dependent Metabolic Disruption in Aging.
Cell-Type Specific Regulation of Cholesterogenesis by CYP46A1 Re-Expression in zQ175 HD Mouse Striatum.
Mitochondrial Dysfunction of Astrocytes Mediates Lipid Accumulation in Temporal Lobe Epilepsy.
Mice prenatally exposed to valproic acid do not show autism-related disorders when fed with polyunsaturated fatty acid-enriched diets.
Succinyl-CoA Synthetase Dysfunction as a Mechanism of Mitochondrial Encephalomyopathy: More than Just an Oxidative Energy Deficit.
SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells.
Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency.
Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function.
The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: A mechanistic review.
DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases.
ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease.
DBDA Matrix Increases Ion Abundance of Fatty Acids and Sulfatides in MALDI-TOF and Mass Spectrometry Imaging Studies.
Fast in vivo assay of creatine kinase activity in the human brain by 31 P magnetic resonance fingerprinting.
Alpha-methyl acetyl-coA racemase deficiency. Magnetic resonance imaging findings of three patients with encephalopathy, epilepsy, and stroke-like episodes.
Mapping trends and hotspots of mitochondrial dysfunction in Alzheimer's disease from 2013 to 2022: a bibliometric analysis of global research.

Annu Rev Neurosci. 2023 07 10. 46 59-78

Cholesterol Metabolism in Aging and Age-Related Disorders.

Gesine Saher.

  All mammalian cell membranes contain cholesterol to maintain membrane integrity. The transport of this hydrophobic lipid is mediated by lipoproteins. Cholesterol is especially enriched in the brain, particularly in synaptic and myelin membranes. Aging involves changes in sterol metabolism in peripheral organs and also in the brain. Some of those alterations have the potential to promote or to counteract the development of neurodegenerative diseases during aging. Here, we summarize the current knowledge of general principles of sterol metabolism in humans and mice, the most widely used model organism in biomedical research. We discuss changes in sterol metabolism that occur in the aged brain and highlight recent developments in cell type-specific cholesterol metabolism in the fast-growing research field of aging and age-related diseases, focusing on Alzheimer's disease. We propose that cell type-specific cholesterol handling and the interplay between cell types critically influence age-related disease processes.

Keywords:  Alzheimer's disease; age-related neurological disease; aging; cholesterol; microglia; neurons

DOI:  https://doi.org/10.1146/annurev-neuro-091922-034237
Microvasc Res. 2023 Jul 10. pii: S0026-2862(23)00111-5. [Epub ahead of print] 104585

Ketone bodies supplementation restores the barrier function, induces a metabolic switch, and elicits beta-hydroxybutyrate diffusion across a monolayer of iPSC-derived brain microvascular endothelial cells.

Pervaiz Iqra, Mehta Yash, Sherill Kinzie, Patel Dhavalkumar, Al-Ahmad Abraham Jacob.

  Glucose constitutes the main source of energy for the central nervous system (CNS), its entry occurring at the blood-brain barrier (BBB) via the presence of glucose transporter 1 (GLUT1). However, under food intake restrictions, the CNS can utilize ketone bodies (KB) as an alternative source of energy. Notably, the relationship between the BBB and KBs and its effect on their glucose metabolism remains poorly understood. In this study, we investigated the effect of glucose deprivation on the brain endothelium in vitro, and supplementation with KBs using induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cell-like cells (iBMECs). Glucose-free environment significantly decreased cell metabolic activity and negatively impacted the barrier function. In addition, glucose deprivation did not increase GLUT1 expression but also resulted in a decrease in glucose uptake and glycolysis. Supplementation of glucose-deprived iBMECs monolayers with KB showed no improvement and even worsened upon treatment with acetoacetate. However, under a hypoglycemic condition in the presence of KBs, we noted a slight improvement of the barrier function, with no changes in glucose uptake. Notably, hypoglycemia and/or KB pre-treatment elicited a saturable beta-hydroxybutyrate diffusion across iBMECs monolayers, such diffusion occurred partially via an MCT1-dependent mechanism. Taken together, our study highlights the importance of glucose metabolism and the reliance of the brain endothelium on glucose and glycolysis for its function, such dependence is unlikely to be covered by KBs supplementation. In addition, KB diffusion at the BBB appeared induced by KB pre-treatment and appears to involve an MCT1-dependent mechanism.

Keywords:  Blood-brain barrier; Glycolysis; Ketone bodies; Stem cells; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.mvr.2023.104585
Nutrients. 2023 Apr 23. pii: 2032. [Epub ahead of print]15(9):

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

Anneloes Martinsen, Rasha N M Saleh, Raphael Chouinard-Watkins, Richard Bazinet, Glenn Harden, James Dick, Noemi Tejera, Matthew G Pontifex, David Vauzour, Anne-Marie Minihane.

  The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Keywords:  Alzheimer’s disease; PUFAs; apolipoprotein E; brain; docosahexaenoic acid; flavonoids; phospholipids

DOI:  https://doi.org/10.3390/nu15092032
Magn Reson Med. 2023 Jul 10.

Longitudinal assessment of mitochondrial dysfunction in acute traumatic brain injury using hyperpolarized [1-13 C]pyruvate.

Edward P Hackett, Jun Chen, Laura Ingle, Sarah Al Nemri, Surendra Barshikar, Marco da Cunha Pinho, Erik J Plautz, Brenda L Bartnik-Olson, Jae Mo Park.

   PURPOSE: [13 C]Bicarbonate formation from hyperpolarized [1-13 C]pyruvate via pyruvate dehydrogenase, a key regulatory enzyme, represents the cerebral oxidation of pyruvate and the integrity of mitochondrial function. The present study is to characterize the chronology of cerebral mitochondrial metabolism during secondary injury associated with acute traumatic brain injury (TBI) by longitudinally monitoring [13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate in rodents.
METHODS: Male Wistar rats were randomly assigned to undergo a controlled-cortical impact (CCI, n = 31) or sham surgery (n = 22). Seventeen of the CCI and 9 of the sham rats longitudinally underwent a 1 H/13 C-integrated MR protocol that includes a bolus injection of hyperpolarized [1-13 C]pyruvate at 0 (2 h), 1, 2, 5, and 10 days post-surgery. Separate CCI and sham rats were used for histological validation and enzyme assays.
RESULTS: In addition to elevated lactate, we observed significantly reduced bicarbonate production in the injured site. Unlike the immediate appearance of hyperintensity on T2 -weighted MRI, the contrast of bicarbonate signals between the injured region and the contralateral brain peaked at 24 h post-injury, then fully recovered to the normal level at day 10. A subset of TBI rats demonstrated markedly increased bicarbonate in normal-appearing contralateral brain regions post-injury.
CONCLUSION: This study demonstrates that aberrant mitochondrial metabolism occurring in acute TBI can be monitored by detecting [13 C]bicarbonate production from hyperpolarized [1-13 C]pyruvate, suggesting that [13 C]bicarbonate is a sensitive in-vivo biomarker of the secondary injury processes.

Keywords:  hyperpolarization; metabolic imaging; mitochondrial dysfunction; pyruvate dehydrogenase; traumatic brain injury

DOI:  https://doi.org/10.1002/mrm.29794
Physiol Res. 2023 Jul 14. 72(3): 403-414

The presence of pyruvate carboxylase in the human brain and its role in the survival of cultured human astrocytes.

E Gondáš, A Kráľová Trančíková, J Šofranko, P Majerová, V Lučanský, M Dohál, A Kováč, R Murín.

Pyruvate carboxylase (PC) is a mitochondrial, biotin-containing enzyme catalyzing the ATP-dependent synthesis of oxaloacetate from pyruvate and bicarbonate, with a critical anaplerotic role in sustaining the brain metabolism. Based on the studies performed on animal models, PC expression was assigned to be glia-specific. To study PC distribution among human neural cells, we probed the cultured human astrocytes and brain sections with antibodies against PC. Additionally, we tested the importance of PC for the viability of cultured human astrocytes by applying the PC inhibitor 3-chloropropane-1,2-diol (CPD). Our results establish the expression of PC in mitochondria of human astrocytes in culture and brain tissue and also into a subpopulation of the neurons in situ. CPD negatively affected the viability of astrocytes in culture, which could be partially reversed by supplementing media with malate, 2-oxoglutarate, citrate, or pyruvate. The provided data estimates PC expression in human astrocytes and neurons in human brain parenchyma. Furthermore, the enzymatic activity of PC is vital for sustaining the viability of cultured astrocytes.
Arch Toxicol. 2023 Jul 13.

Developmental brain lipidomics is influenced by postnatal chlorpyrifos exposure and APOE genetic background in mice.

Laia Guardia-Escote, Judit Biosca-Brull, Maria Cabré, Jordi Blanco, Mikaela Mladenova-Koleva, Pia Basaure, Cristian Pérez-Fernández, Fernando Sánchez-Santed, José L Domingo, Maria Teresa Colomina.

  Lipids are a major component of the brain, and are involved in structural and neurodevelopmental processes such as neurogenesis, synaptogenesis and signaling. Apolipoprotein E (apoE) is the main lipoprotein involved in lipid transport in the brain. The apoE isoforms can determine vulnerability to the toxic effects of the pesticide chlorpyrifos (CPF), which can interfere with normal neurodevelopment. We aimed to study the effects of postnatal exposure to CPF and of the APOE genotype on the lipid composition of the brain at early ages. For it, we used apoE3 and apoE4 targeted-replacement (TR) male mice, as well as wild-type C57BL/6. The mice were orally exposed to 1 mg/kg/day of CPF on postnatal days 10-15 and, four hours after the treatment, we obtained samples to assess the cerebral lipid composition. Differences between APOE genotypes were found in the cerebral lipid profile in the postnatal period. ApoE4-TR mice exhibited higher lipid concentrations compared to the other groups in most of the cases. CPF exposure led to a decrease in cholesteryl ester and triglyceride concentrations, while modulating the levels of phosphatidylcholine species based on the apoE isoform. Specifically, CPF treatment decreased the concentration of some species of this lipid (PC30:0, PC31:0, PC32:2, PC36:5, PC40:4 and PC40:5) in C57BL/6 mice exposed to CPF, increased (PC31:0 and PC37:6) in apoE3-TR exposed mice while exposed apoE4-TR mice remained unaltered. These results provide further insights into the lipid composition of the brain at early ages, and how it can be modulated by environmental and genetic factors.

Keywords:  APOE; Brain development; Chlorpyrifos; Lipidomics

DOI:  https://doi.org/10.1007/s00204-023-03555-8
Nat Commun. 2023 07 10. 14(1): 4070

Establishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system.

Albert Suades, Aziz Qureshi, Sarah E McComas, Mathieu Coinçon, Axel Rudling, Yurie Chatzikyriakidou, Michael Landreh, Jens Carlsson, David Drew.

Glucose transporters (GLUTs) are essential for organism-wide glucose homeostasis in mammals, and their dysfunction is associated with numerous diseases, such as diabetes and cancer. Despite structural advances, transport assays using purified GLUTs have proven to be difficult to implement, hampering deeper mechanistic insights. Here, we have optimized a transport assay in liposomes for the fructose-specific isoform GLUT5. By combining lipidomic analysis with native MS and thermal-shift assays, we replicate the GLUT5 transport activities seen in crude lipids using a small number of synthetic lipids. We conclude that GLUT5 is only active under a specific range of membrane fluidity, and that human GLUT1-4 prefers a similar lipid composition to GLUT5. Although GLUT3 is designated as the high-affinity glucose transporter, in vitro D-glucose kinetics demonstrates that GLUT1 and GLUT3 actually have a similar KM, but GLUT3 has a higher turnover. Interestingly, GLUT4 has a high KM for D-glucose and yet a very slow turnover, which may have evolved to ensure uptake regulation by insulin-dependent trafficking. Overall, we outline a much-needed transport assay for measuring GLUT kinetics and our analysis implies that high-levels of free fatty acid in membranes, as found in those suffering from metabolic disorders, could directly impair glucose uptake.

DOI: https://doi.org/10.1038/s41467-023-39711-y
Mol Neurobiol. 2023 Jul 14.

N-Acetyl Serotonin Provides Neuroprotective Effects by Inhibiting Ferroptosis in the Neonatal Rat Hippocampus Following Hypoxic Brain Injury.

Xiaomei Yang, Yue Yang, Feng Gao, Kangping Lu, Chunling Wang.

  Hypoxic-ischemic encephalopathy is the main cause of infant brain damage, perinatal death, and chronic neonatal disability worldwide. Ferroptosis is a new form of cell death that is closely related to hypoxia-induced brain damage. N-Acetyl serotonin (NAS) exerts neuroprotective effects, but its effects and underlying mechanisms in hypoxia-induced brain damage remain unclear. In the present study, 5-day-old neonatal Sprague-Dawley rats were exposed to hypoxia for 7 days to establish a hypoxia model. Histochemical staining was used to measure the effects of hypoxia on the rat hippocampus. The hippocampal tissue in the hypoxia group showed significant atrophy. Hypoxia significantly increased the levels of prostaglandin-endoperoxide synthase 2 (PTGS2) and the iron metabolism-related protein transferrin receptor 1 (TfR1) and decreased the levels of glutathione peroxidase 4 (GPX4). These changes resulted in mitochondrial damage, causing neuronal ferroptosis in the hippocampus. More importantly, NAS may improve mitochondrial function and alleviate downstream ferroptosis and damage to the hippocampus following hypoxia. In conclusion, we found that NAS could suppress neuronal ferroptosis in the hippocampus following hypoxic brain injury. These discoveries highlight the potential use of NAS as a treatment for neuronal damage through the suppression of ferroptosis, suggesting new treatment strategies for hypoxia-induced brain damage.

Keywords:  Ferroptosis; Hypoxia-induced brain injury; Hypoxic-ischemic encephalopathy; N-Acetyl serotonin

DOI:  https://doi.org/10.1007/s12035-023-03464-y
Nat Metab. 2023 Jul 10.

Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.

Yi-Heng Tai, Daniel Engels, Giuseppe Locatelli, Ioanna Emmanouilidis, Caroline Fecher, Delphine Theodorou, Stephan A Müller, Simon Licht-Mayer, Mario Kreutzfeldt, Ingrid Wagner, Natalia Prudente de Mello, Sofia-Natsouko Gkotzamani, Laura Trovò, Arek Kendirli, Almir Aljović, Michael O Breckwoldt, Ronald Naumann, Florence M Bareyre, Fabiana Perocchi, Don Mahad, Doron Merkler, Stefan F Lichtenthaler, Martin Kerschensteiner, Thomas Misgeld.

Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

DOI: https://doi.org/10.1038/s42255-023-00838-3
Dev Neurobiol. 2023 Jul 12.

Lipid peroxidation and neuroinflammation: A possible link between maternal fructose intake and delay of acquisition of neonatal reflexes in Wistar female rats.

Facundo H Prado Spalm, Marié L Cuervo Sánchez, Natalia E Furland, Ana S Vallés.

  Fructose is a common sweetener found in the daily diet supplemented to many processed and ultra-processed foods and beverages. Consumption of fructose-sweetened beverages has drastically increased in the last decades and is widely associated with metabolic disease, systemic pro-inflammatory status, and adverse transgenerational effects. To date, the impact of maternal fructose intake in brain function of the offspring is less explored. Therefore, the aim of this study was first, to investigate adverse effects in developmental milestones of the progeny of mothers with metabolic syndrome (MetS), induced by ad libitum consumption of a 20% fructose solution, and second to identify possible molecular changes in the nervous system of the newborns associated with maternal fructose intake. Wistar rats were randomly separated into two groups with access to water or fructose (20% w/v in water) for 10 weeks. After MetS was confirmed, dams were mated with control males and continued drinking water or fructose solution during gestation. At postnatal day (PN) 1, a subgroup of offspring of each sex was sacrificed and brains were dissected for oxidative stress and inflammatory status analysis. Changes in the developmental milestones due to maternal fructose consumption were studied (PN3-PN21) in another subgroup of offspring. Sexually dimorphic effects were found on the progeny's acquisition of neurodevelopmental milestones, in brain lipid peroxidation, neuroinflammation, and antioxidative defensive response. Our results suggest that dams' MetS, induced by fructose intake, disrupts brain redox homeostasis in female offspring and affects sensorimotor brain circuitry which may have a translational value for studying neurodevelopmental diseases.

Keywords:  fructose; lipid peroxidation; metabolic syndrome; neurodevelopment; neuroinflammation; offspring

DOI:  https://doi.org/10.1002/dneu.22921
J Psychiatry Neurosci. 2023 Jul-Aug;48(4):48(4): E295-E304

Abnormal cerebral metabolism and metabolic connectivity in individuals with heroin dependence: an integrated resting-state PET/fMRI study in large-scale networks.

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

BACKGROUND: Increasing evidence suggests that heroin addiction may be related to the dysfunction among the triple brain network (default mode network [DMN], salience network [SN] and executive control network [ECN]). However, the characteristics of glucose metabolism and metabolic connectivity among core regions of the triple brain network remain unknown. Therefore, we hypothesized that individuals with heroin dependence would show abnormal glucose metabolism and accompanied abnormal metabolic connectivity within the triple brain network.
METHODS: Individuals with heroin dependence and healthy controls matched for age and sex underwent integrated positron emission tomography/magnetic resonance imaging (PET/MRI). Differences in glucose metabolism and metabolic connectivity among the DMN, SN and ECN were analyzed based on 18F-fluorodeoxyglucose PET and resting-state fMRI data.
RESULTS: We included 36 individuals with heroin dependence and 30 matched healthy controls in our study. The heroin dependence group showed a significant reduction of glucose metabolism in the bilateral anterior insula (AI) and inferior parietal lobule (IPL), and a significantly decreased metabolic connectivity between the right AI and the left dorsolateral prefrontal cortex (DLPFC). The daily dose of methadone was negatively correlated with glucose metabolism of the right AI and right IPL.
LIMITATIONS: The results revealed the glucose metabolism alterations and metabolic connectivity only within the triple brain network in individuals with heroin dependence; additional brain networks should be investigated in future studies. Although methadone is an opioid with a similar neurophysiological mechanism as heroin, the specific chronic effects of methadone on cerebral metabolism and metabolic connectivity should also be investigated in future studies.
CONCLUSION: Our findings suggest that long-term opioid use might, to some extent, be associated with reduced synergistic ability between the SN and ECN, which may be associated with the dysfunction of cognitive control. In particular, the right AI, which showed hypometabolism and related reduction in SN-ECN metabolic connectivity, should receive increasing attention in future studies.

DOI: https://doi.org/10.1503/jpn.220171
Int J Mol Sci. 2023 Jun 22. pii: 10483. [Epub ahead of print]24(13):

Adult-Onset CNS Sulfatide Deficiency Causes Sex-Dependent Metabolic Disruption in Aging.

Shulan Qiu, Sijia He, Jianing Wang, Hu Wang, Anindita Bhattacharjee, Xin Li, Moawiz Saeed, Jeffrey L Dupree, Xianlin Han.

  The interconnection between obesity and central nervous system (CNS) neurological dysfunction has been widely appreciated. Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose-intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found that increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypothalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food intake.

Keywords:  Alzheimer’s disease; aging; food intake; glucose metabolism; sulfatide

DOI:  https://doi.org/10.3390/ijms241310483
Int J Mol Sci. 2023 Jul 02. pii: 11001. [Epub ahead of print]24(13):

Cell-Type Specific Regulation of Cholesterogenesis by CYP46A1 Re-Expression in zQ175 HD Mouse Striatum.

Katleen Pinchaud, Chloé Masson, Baptiste Dayre, Coline Mounier, Jean-François Gilles, Peter Vanhoutte, Jocelyne Caboche, Sandrine Betuing.

  Cholesterol metabolism dysregulation is associated with several neurological disorders. In Huntington's disease (HD), several enzymes involved in cholesterol metabolism are downregulated, among which the neuronal cholesterol 24-hydroxylase, CYP46A1, is of particular interest. The restoration of CYP46A1 expression in striatal neurons of HD mouse models is beneficial for motor behavior, cholesterol metabolism, transcriptomic activity, and alleviates neuropathological hallmarks induced by mHTT. Among the genes regulated after CYP46A1 restoration, those involved in cholesterol synthesis and efflux may explain the positive effect of CYP46A1 on cholesterol precursor metabolites. Since cholesterol homeostasis results from a fine-tuning between neurons and astrocytes, we quantified the distribution of key genes regulating cholesterol metabolism and efflux in astrocytes and neurons using in situ hybridization coupled with S100β and NeuN immunostaining, respectively. Neuronal expression of CYP46A1 in the striatum of HD zQ175 mice increased key cholesterol synthesis driver genes (Hmgcr, Dhcr24), specifically in neurons. This effect was associated with an increase of the srebp2 transcription factor gene that regulates most of the genes encoding for cholesterol enzymes. However, the cholesterol efflux gene, ApoE, was specifically upregulated in astrocytes by CYP46A1, probably though a paracrine effect. In summary, the neuronal expression of CYP46A1 has a dual and specific effect on neurons and astrocytes, regulating cholesterol metabolism. The neuronal restoration of CYP46A1 in HD paves the way for future strategies to compensate for mHTT toxicity.

Keywords:  ApoE; CYP46A1; Dhrc24; Hmgcr; Huntington’s disease; Srebp2; cholesterol; fluorescence in situ hybridization coupled with immunostaining; gene regulation; striatum

DOI:  https://doi.org/10.3390/ijms241311001
Aging Dis. 2023 Jul 11.

Mitochondrial Dysfunction of Astrocytes Mediates Lipid Accumulation in Temporal Lobe Epilepsy.

Yang Su, Meng Tang, Minjin Wang.

Lipid-accumulated reactive astrocytes (LARAs) have recently been confirmed to be a pivotal cell type present in temporal lobe epilepsy (TLE) lesions. These cells not only induce anomalous lipid accumulation within the epileptic foci but also decrease the seizure threshold by employing upregulated activation of the adenosine A2A receptor (A2AR). Furthermore, disturbances in mitochondrial oxidative phosphorylation (OxPhos) have been noted as significant drivers of lipid accumulation in astrocytes. Moreover, the deficiency of OxPhos in astrocytes can induce severe neuroinflammation, which can worsen the progression of TLE. Accordingly, further exploration of the correlation between mitochondrial dysfunction, LARAs-mediated lipid accumulation, and A2AR activation within epilepsy lesions is warranted. It could potentially elucidate the vital role of mitochondrial dysfunction in the pathogenesis of TLE.

DOI: https://doi.org/10.14336/AD.2023.0624
Sci Rep. 2023 07 11. 13(1): 11235

Mice prenatally exposed to valproic acid do not show autism-related disorders when fed with polyunsaturated fatty acid-enriched diets.

Valentine Turpin, Maud Schaffhauser, Mathieu Thabault, Agnès Aubert, Corinne Joffre, Eric Balado, Jean-Emmanuel Longueville, Maureen Francheteau, Christophe Burucoa, Maxime Pichon, Sophie Layé, Mohamed Jaber.

Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in ameliorating cardinal symptoms of the disease remain elusive. Here, we compared a n-3 long-chain (LC) PUFA dietary supplementation (n-3 supp) obtained from fatty fish with a n-3 PUFA precursor diet (n-3 bal) obtained from plant oils in the valproic acid (VPA, 450 mg/kg at E12.5) ASD mouse model starting from embryonic life, throughout lactation and until adulthood. Maternal and offspring behaviors were investigated as well as several VPA-induced ASD biological features: cerebellar Purkinje cell (PC) number, inflammatory markers, gut microbiota, and peripheral and brain PUFA composition. Developmental milestones were delayed in the n-3 supp group compared to the n-3 bal group in both sexes. Whatever the diet, VPA-exposed offspring did not show ASD characteristic alterations in social behavior, stereotypies, PC number, or gut microbiota dysbiosis while global activity, gait, peripheral and brain PUFA levels as well as cerebellar TNF-alpha levels were differentially altered by diet and treatment according to sex. The current study provides evidence of beneficial effects of n-3 PUFA based diets, including one without LCPUFAs, on preventing several behavioral and cellular symptoms related to ASD.

DOI: https://doi.org/10.1038/s41598-023-38423-z
Int J Mol Sci. 2023 Jun 27. pii: 10725. [Epub ahead of print]24(13):

Succinyl-CoA Synthetase Dysfunction as a Mechanism of Mitochondrial Encephalomyopathy: More than Just an Oxidative Energy Deficit.

Makayla S Lancaster, Brett H Graham.

  Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. SCS-deficient encephalomyopathy typically presents in infancy and early childhood, with many patients succumbing to the disease during childhood. Common symptoms include abnormal brain MRI, basal ganglia lesions and cerebral atrophy, severe hypotonia, dystonia, progressive psychomotor regression, and growth deficits. Although subunits of SCS were first identified as causal genes for progressive metabolic encephalomyopathy in the early 2000s, recent investigations are now beginning to unravel the pathomechanisms underlying this metabolic disorder. This article reviews the current understanding of SCS function within and outside the TCA cycle as it relates to the complex and multifactorial mechanisms underlying SCS-related mitochondrial encephalomyopathy.

Keywords:  encephalomyopathy; mitochondria; mitochondrial DNA; protein succinylation; succinyl-CoA synthetase; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/ijms241310725
Cell Rep. 2023 Jul 11. pii: S2211-1247(23)00801-X. [Epub ahead of print]42(7): 112790

SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells.

Feng Geng, Yaogang Zhong, Huali Su, Etienne Lefai, Shino Magaki, Timothy F Cloughesy, William H Yong, Arnab Chakravarti, Deliang Guo.

  Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.

Keywords:  ATG4A; ATG9B; CP: Cancer; CP: Metabolism; LC3B; NPC2; SREBP-1; autophagy; cholesterol homeostasis; cholesteryl esters; glioblastoma; lipid droplets

DOI:  https://doi.org/10.1016/j.celrep.2023.112790
Sci Rep. 2023 Jul 14. 13(1): 11414

Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency.

K L Stauch, S Totusek, A J Trease, L D Estrella, K Emanuel, A Fangmeier, H S Fox.

Our study utilizes a longitudinal isotopic metabolic labeling approach in vivo in combination with organelle fraction proteomics to address the role of parkin in mitochondrial protein turnover in mice. The use of metabolic labeling provides a method to quantitatively determine the global changes in protein half-lives whilst simultaneously assessing protein expression. Studying two diverse mitochondrial populations, we demonstrated the median half-life of brain striatal synaptic mitochondrial proteins is significantly greater than that of hepatic mitochondrial proteins (25.7 vs. 3.5 days). Furthermore, loss of parkin resulted in an overall, albeit modest, increase in both mitochondrial protein abundance and half-life. Pathway and functional analysis of our proteomics data identified both known and novel pathways affected by loss of parkin that are consistent with its role in both mitochondrial quality control and neurodegeneration. Our study therefore adds to a growing body of evidence suggesting dependence on parkin is low for basal mitophagy in vivo and provides a foundation for the investigation of novel parkin targets.

DOI: https://doi.org/10.1038/s41598-023-38484-0
Cell Rep. 2023 Jul 11. pii: S2211-1247(23)00787-8. [Epub ahead of print]42(7): 112776

Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function.

Sriparna Ghosal, Elias Gebara, Eva Ramos-Fernández, Alessandro Chioino, Jocelyn Grosse, Isabelle Guillot de Suduiraut, Olivia Zanoletti, Bernard Schneider, Antonio Zorzano, Simone Astori, Carmen Sandi.

  The nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc links anxiety with social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons regulates anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show decreased accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by decreased accumbal mitochondrial functions and decreased excitability in D2-MSNs. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently and likely because of an increase in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.

Keywords:  CP: Neuroscience; anxiety; medium spiny neurons; mitochondria; mitofusin 2; motivation; nucleus accumbens; social competition; social dominance; tube test

DOI:  https://doi.org/10.1016/j.celrep.2023.112776
Expert Opin Ther Targets. 2023 Jul 10.

The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: A mechanistic review.

Tahere Paseban, Mohaddeseh Sadat Alavi, Leila Etemad, Ali Roohbakhsh.

   INTRODUCTION: Cholesterol homeostasis is critical for normal brain function. It is tightly controlled by various biological elements. ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that effluxes cholesterol from cells, particularly astrocytes, into the extracellular space. The recent studies pertaining to ABCA1's role in CNS disorders were included in this study.
AREAS COVERED: In this comprehensive literature review, preclinical and human studies showed that ABCA1 has a significant role in the following diseases or disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, neuropathy, anxiety, depression, psychosis, epilepsy, stroke, and brain ischemia and trauma.
EXPERT OPINION: ABCA1 via modulating normal and aberrant brain functions such as apoptosis, phagocytosis, BBB leakage, neuroinflammation, amyloid β efflux, myelination, synaptogenesis, neurite outgrowth, and neurotransmission promotes beneficial effects in aforementioned diseases. ABCA1 is a key molecule in the CNS. By boosting its expression or function, some CNS disorders may be resolved. In preclinical studies, liver X receptor agonists have shown promise in treating CNS disorders via ABCA1 and apoE enhancement.

Keywords:  ABCA1; Alzheimer’s disease; Apoptosis; Neuroinflammation; Neurological disorders; Stroke

DOI:  https://doi.org/10.1080/14728222.2023.2235718
Int J Mol Sci. 2023 Jun 27. pii: 10717. [Epub ahead of print]24(13):

DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases.

Christina Kousparou, Maria Fyrilla, Anastasis Stephanou, Ioannis Patrikios.

  Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing.

Keywords:  Alzheimer’s disease; EPA/DHA/LA/GLA; Huntington’s disease; PUFA; Parkinson’s disease; amyotrophic lateral sclerosis; clinical trials; multiple sclerosis; omega-3; omega-6; polyunsaturated

DOI:  https://doi.org/10.3390/ijms241310717
Mol Neurodegener. 2023 07 12. 18(1): 47

ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease.

Yingbin Lin, Anlan Lin, Lili Cai, Weibin Huang, Shanzhi Yan, Yuanxiang Wei, Xinglin Ruan, Wenting Fang, Xiaoman Dai, Jinbo Cheng, Jie Zhang, Wanjin Chen, Qinyong Ye, Xiaochun Chen, Jing Zhang.

   BACKGROUND: Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood.
METHODS: We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice.
RESULTS: We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner.
CONCLUSION: ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.

Keywords:  ACSS2; Acetate; Alzheimer’s disease; Glutamate receptors; Histone acetylation; Synaptic plasticity

DOI:  https://doi.org/10.1186/s13024-023-00625-4
J Am Soc Mass Spectrom. 2023 Jul 09.

DBDA Matrix Increases Ion Abundance of Fatty Acids and Sulfatides in MALDI-TOF and Mass Spectrometry Imaging Studies.

Nigina Khamidova, Melissa R Pergande, Koralege C Pathmasiri, Rida Khan, Justin T Mohr, Stephanie M Cologna.

MALDI-TOF MS is a powerful tool to analyze biomolecules, owing to its soft ionization nature that generally results in simple spectra of singly charged ions. Implementation of the technology in the imaging mode provides a means to spatially map analytes in situ. Recently, a new matrix, DBDA (N1,N4-dibenzylidenebenzene-1,4-diamine) was reported to facilitate the ionization of free fatty acids in negative ion mode. Building on this finding, we sought to implement DBDA for MALDI mass spectrometry imaging studies in brain tissue and successfully map oleic acid, palmitic acid, stearic acid, docosahexaenoic acid, and arachidonic acid using mouse brain sections. Moreover, we hypothesized that DBDA would provide superior ionization for sulfatides, a class of sulfolipids with multiple biological functions. Herein, we also demonstrate that DBDA is ideal for MALDI mass spectrometry imaging of fatty acids and sulfatides in brain tissue sections. Additionally, we show enhanced ionization of sulfatides using DBDA compared with three different traditionally used MALDI matrices. Together these results provide new opportunities for studies to measure sulfatides by MALDI-TOF MS.

DOI: https://doi.org/10.1021/jasms.3c00061
NMR Biomed. 2023 Jul 09. e4998

Fast in vivo assay of creatine kinase activity in the human brain by 31 P magnetic resonance fingerprinting.

Mark Widmaier, Song-I Lim, Daniel Wenz, Lijing Xin.

  A new and efficient magnetisation transfer 31 P magnetic resonance fingerprinting (MT-31 P-MRF) approach is introduced to measure the creatine kinase metabolic rate kCK$$ {k}_{\mathrm{CK}} $$ between phosphocreatine (PCr) and adenosine triphosphate (ATP) in human brain. The MRF framework is extended to overcome challenges in conventional 31 P measurement methods in the human brain, enabling reduced acquisition time and specific absorption rate (SAR). To address the challenge of creating and matching large multiparametric dictionaries in an MRF scheme, a nested iteration interpolation method (NIIM) is introduced. As the number of parameters to estimate increases, the size of the dictionary grows exponentially. NIIM can reduce the computational load by breaking dictionary matching into subsolutions of linear computational order. MT-31 P-MRF combined with NIIM provides T1PCr$$ {T}_1^{\mathrm{PCr}} $$ , T1ATP$$ {T}_1^{\mathrm{ATP}} $$ and kCK$$ {k}_{\mathrm{CK}} $$ estimates in good agreement with those obtained by the exchange kinetics by band inversion transfer (EBIT) method and literature values. Furthermore, the test-retest reproducibility results showed that MT-31 P-MRF achieves a similar or better coefficient of variation (<12%) for T1ATP$$ {T}_1^{\mathrm{ATP}} $$ and kCK$$ {k}_{\mathrm{CK}} $$ measurements in 4 min 15 s, than EBIT with 17 min 4 s scan time, enabling a fourfold reduction in scan time. We conclude that MT-31 P-MRF in combination with NIIM is a fast, accurate, and reproducible approach for in vivo kCK$$ {k}_{\mathrm{CK}} $$ assays in the human brain, which enables the potential to investigate energy metabolism in a clinical setting.

Keywords:  31P MRS; MRF; brain energy metabolism; creatine kinase

DOI:  https://doi.org/10.1002/nbm.4998
Neuroradiol J. 2023 Jul 15. 19714009231187342

Alpha-methyl acetyl-coA racemase deficiency. Magnetic resonance imaging findings of three patients with encephalopathy, epilepsy, and stroke-like episodes.

Maria I Palacio-Montoya, Diego A Herrera, Sergio A Vargas, Mauricio Castillo.

  Alpha-methyl acyl-CoA racemase deficiency (AMACRD) is a rare peroxisomal disorder that results in the accumulation of pristanic acid and 16 cases have been reported in the literature. Here, we present three additional patients, two confirmed by genomic study and one suspected. Three siblings who were born to healthy unrelated parents developed recurrent episodes of encephalopathy, seizures, and behavioral disturbances. In all 3, brain MRI showed lesions in the thalami, cerebral peduncles, and mesencephalic tegmentum, as well as brain volume loss. In addition, one patient had a chronic hemispheric infarct and an acute contralateral infarct, and another had a subacute infarct involving multiple vascular territories without abnormalities on MR angiography.

Keywords:  Alpha-methyl acetyl-coA racemase; dysfunction; encephalopathy; epilepsy; single peroxisomal

DOI:  https://doi.org/10.1177/19714009231187342
Front Neurosci. 2023 ;17 1199625

Mapping trends and hotspots of mitochondrial dysfunction in Alzheimer's disease from 2013 to 2022: a bibliometric analysis of global research.

Wang Guo, Liban Abdulle Hassan, Yu-Hao Chu, Xue-Ping Yang, Sheng-Xue Wang, Han-Xiao Zhu, Yun Li.

   Objective: Alzheimer's disease (AD), a prevalent neurodegenerative affliction that predominantly affects the elderly population, imposes a substantial burden on not only patients but also their families and society at large. Mitochondrial dysfunction plays an important role in its pathogenesis. In this study, we conducted a bibliometric analysis of research on mitochondrial dysfunction and AD over the past 10 years, with the aim of summarizing current research hotspots and trends in this field.
Methods: On February 12, 2023, we searched for publications about mitochondrial dysfunction and AD in the Web of Science Core Collection database from 2013 to 2022. VOSview software, CiteSpace, SCImago, and RStudio were used to analyze and visualize countries, institutions, journals, keywords, and references.
Results: The number of publications on mitochondrial dysfunction and AD were on the rise until 2021 and decreased slightly in 2022. The United States ranks first in the number of publications, H-index, and intensity of international cooperation in this research. In terms of institutions, Texas Tech University in the United States has the most publications. The Journal of Alzheimer's Disease has the most publications in this field of research, while Oxidative Medicine and Cellular Longevity have the highest number of citations. Mitochondrial dysfunction is still an important direction of current research. Autophagy, mitochondrial autophagy, and neuroinflammation are new hotspots. The article from Lin MT is the most cited by analyzing references.
Conclusion: Research on mitochondrial dysfunction in AD is gaining significant momentum as it provides a crucial research avenue for the treatment of this debilitating condition. This study sheds light on the present research trajectory concerning the molecular mechanisms underlying mitochondrial dysfunction in AD.

Keywords:  Alzheimer’s disease; CiteSpace; VOSview; Web of Science; bibliometric; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fnins.2023.1199625