bims-medebr 2025-07-13 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–07–13
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University

Tracking Hyperpolarized [1-13C] Pyruvate and [1-13C] L-Lactate Metabolism in the Healthy and Post-Stroke Mouse Brain.
Implications of mitochondrial phosphatidylethanolamine in neuronal health and neurodegeneration.
Palmitic acid-induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration.
Beta-hydroxybutyrate counteracts the deleterious effects of a saturated high-fat diet on synaptic AMPAR receptors and cognitive performance.
Glycogen supports glycolytic plasticity in neurons.
Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration.
Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).
A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions.
Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4.
PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits.
Assessing the developmental effects of fentanyl and impacts on lipidomic profiling using neural stem cell models.
Nervonic acid in infant nutrition: a forward-looking approach to enhancing neurodevelopmental outcomes.
Mapping of neurovascular and neurometabolic couplings by multimodal optical imaging.
Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.
Loss of PLA2G4E compromises synaptic structure and cognitive outcomes in mice.

NMR Biomed. 2025 Aug;38(8): e70094

Tracking Hyperpolarized [1-13C] Pyruvate and [1-13C] L-Lactate Metabolism in the Healthy and Post-Stroke Mouse Brain.

Thanh Phong Lê, Lara Buscemi, Mario Lepore, Elise Vinckenbosch, Bernard Lanz, Rolf Gruetter, Lorenz Hirt, Jean-Noël Hyacinthe, Mor Mishkovsky.

Tracking hyperpolarized (HP) 13C labeling from either [1-13C] pyruvate or [1-13C] lactate is a useful tool to assess intermediary metabolism in vivo, which has already been translated from preclinical to clinical research. HP [1-13C] pyruvate and [1-13C] lactate provide complementary views on the same metabolic pathway, and both have been tested as potential neuroprotective agents in the context of acute brain injuries, with more convincing evidence for a beneficial effect of lactate. Our aim here was to investigate and compare HP [1-13C] pyruvate and [1-13C] lactate performance as metabolic contrast agents in the brains of healthy mice and mice subjected to middle cerebral artery occlusion, a model of ischemic stroke. We analyzed the metabolite ratios and quantified the real-time apparent kinetic rates of their cerebral metabolism. We found that the cerebral metabolism of both HP [1-13C] pyruvate and HP [1-13C] lactate showed significant alterations after transient cerebral ischemia in mice, reflecting the damage as well as the metabolic reprogramming set in motion to meet the energetic demands in the acute phase of stroke. There was a significant decrease in metabolite ratios (cLPR, cAPR for pyruvate bolus and cPLR, cALR for lactate bolus) and kinetic rates (ckPL for pyruvate bolus and ckLP for lactate bolus). These values progressively decreased from sham to 1 h and 2 h after reperfusion measurements. Overall, while pyruvate is better established as an imaging probe, and lactate appears advantageous on the therapeutic side, both bring information to interrogate brain metabolism in physiological and pathophysiological conditions in real time. This study prepares the ground for further investigation to fully exploit the potential of HP metabolic contrasts for stroke theranostics.

DOI: https://doi.org/10.1002/nbm.70094
Neural Regen Res. 2025 Jul 05.

Implications of mitochondrial phosphatidylethanolamine in neuronal health and neurodegeneration.

Yantao Zuo, Niharika Amireddy, Qian Cai.

  Phosphatidylethanolamine is a major phospholipid class abundant in the brain, particularly in the inner leaflet of the plasma and mitochondrial membranes. Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum, phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum. Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions. Neurons are highly enriched with phosphatidylethanolamine, and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer's disease, Parkinson's disease, and hereditary spastic paraplegia, among other neurological disorders. Indeed, disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases, highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons. In this review, we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria. We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases. Finally, we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.

Keywords:  ; Alzheimer's disease; Parkinson's disease; autophagy; cognitive dysfunction; hereditary spastic paraplegia; neuronal phospholipid trafficking; phosphatidylserine decarboxylase; phosphatidylserine transport; tauopathy

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00201
Neural Regen Res. 2025 Jul 05.

Palmitic acid-induced autolysosomal dysfunction and lipotoxicity in neuroinflammation and neurodegeneration.

Eka Norfaishanty Saipuljumri, Jialiu Zeng, Chih Hung Lo.

  Neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are increasingly associated with metabolic dysfunction, including obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease. Central to this connection is the dysregulation of lipid metabolism, which extends beyond peripheral tissues to the brain, defective autolysosomal function, oxidative stress, inflammation, and insulin resistance. Lipids, which constitute over half of dry weight of the brain, play critical roles in energy provision, structural integrity, and synaptic function. Dysregulation of lipid metabolism contributes to neuroinflammation, impaired neuronal function, and disrupted blood-brain barrier integrity. Palmitic acid, a saturated fatty acid abundant in high-fat diets, serves as a key model for studying lipid-induced toxicity (lipotoxicity) in the brain. Palmitic acid disrupts autophagy and lysosomal function, mitochondrial function, triggering oxidative stress, contributing to neuroinflammation and neurodegeneration. These effects are particularly pronounced in neurons, which are highly susceptible to lipid-induced toxicity due to their high metabolic demands. Glial cells, including astrocytes, microglia, and oligodendrocytes, also exhibit distinct vulnerabilities and adaptive responses to lipid metabolism dysregulation, further contributing to neuroinflammation and demyelination. Therapeutic strategies, such as supplementation with polyunsaturated fatty acids, AMP-activated protein kinase activation, and lysosome-targeted interventions, show promise in mitigating palmitic acid-induced lipotoxicity and restoring cellular homeostasis. This review comprehensively examines palmitic acid-induced lipotoxicity and its impact on autolysosomal dysfunction across various central nervous system cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Additionally, it highlights therapeutic approaches to restore autolysosomal function under lipotoxic conditions. Advances in multi-omics technologies and a deeper understanding of intercellular crosstalk offer new avenues for developing targeted therapies to restore autolysosomal function, and attenuate neuroinflammation and neurodegeneration.

Keywords:  autolysosomal dysfunction; lipotoxicity; metabolic dysfunction; neuroinflammation; palmitic acid

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00432
Mol Metab. 2025 Jul 06. pii: S2212-8778(25)00114-0. [Epub ahead of print] 102207

Beta-hydroxybutyrate counteracts the deleterious effects of a saturated high-fat diet on synaptic AMPAR receptors and cognitive performance.

Rocío Rojas, Christian Griñán-Ferré, Aida Castellanos, Ernesto Griego, Marc Martínez, Juan de Dios Navarro-López, Lydia Jiménez-Díaz, José Rodríguez-Álvarez, David Soto Del Cerro, Pablo E Castillo, Mercè Pallàs, Núria Casals, Rut Fadó.

  The ketogenic diet -high in fat and low in carbohydrates- and intermittent fasting have gained popularity not only for weight management but also for their potential to delay cognitive decline associated with neurodegenerative diseases and aging. However, adherence to these diets remains low due to their restrictive nature and undesirable side effects. Both dietary approaches stimulate hepatic production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons. Here, we investigated whether BHB supplementation could mitigate AMPA receptor trafficking impairments, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as a saturated fat-rich diet. Our results show that, in cultured primary cortical neurons, exposure to palmitic acid decreases surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids and BHB increase these levels. Furthermore, physiological concentrations of BHB (1-2 mM) countered the adverse effects of palmitic acid on synaptic GluA1 and GluA2 levels in hippocampal neurons, restoring AMPA receptor-mediated synaptic transmission. In hippocampal slices, BHB also reversed palmitate-induced impairments in excitability and synaptic plasticity (long-term potentiation; LTP). Additionally, daily intragastric administration of BHB (100 mg/kg/day for two months) prevented deficits in recognition and spatial memory induced by a saturated fat-rich diet (49% of calories from fat) in mice. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptor abundance, synaptic function, and neuroplasticity, shedding light on the potential use of BHB as a dietary supplement to counteract cognitive impairments linked to metabolic diseases.

Keywords:  AMPA receptor; beta-hydroxybutyrate; memory; palmitic acid; saturated fatty acid-rich diet; synaptic plasticity

DOI:  https://doi.org/10.1016/j.molmet.2025.102207
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2509003122

Glycogen supports glycolytic plasticity in neurons.

Milind Singh, Aaron D Wolfe, Anjali A Vishwanath, Anastasia Tsives, Ian J Gonzalez, Sarah E Emerson, Richard Goodman, Daniel Colón-Ramos.

  Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood. We established a system in Caenorhabditis elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia. We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity. We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity. We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the loss of GDGP impairs glycolytic plasticity and is associated with defects in synaptic vesicle recycling during hypoxia. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function.

Keywords:  C. elegans; glycogen utilization; glycolytic biosensor; glycolytic plasticity; neuronal metabolism

DOI:  https://doi.org/10.1073/pnas.2509003122
Cell Death Dis. 2025 Jul 07. 16(1): 499

Homocysteine interferes with Ndufa1 leading to mitochondrial dysfunction through repression of the NAD+/Sirt1 pathway in the brain: a possible link between hyperhomocysteinemia and neurodegeneration.

Gaoshang Chai, Yuming Mao, Juan Gong, Shuguang Bi, Yuqi Zhang, Jiajun Wu, Liu Yang, Tianlong Gao, Haitian Fu, Chunjing Yu, Caili Ren, Guofu Zhang, Xuming Zhu, Xin Guan, Haoting Yu, Caijing Tang, Yunjuan Nie, Haitao Yu.

Mitochondrial defects are early pathological changes in neurodegenerative disease (ND). Homocysteine (Hcy) is an independent risk factor for ND. However, whether and how Hcy induces mitochondrial defects during the process of neurodegeneration is unclear. Here, we revealed that Hcy interfered with mitochondrial oxidative phosphorylation (OXPHOS) by inhibiting the mitochondrial electron transport chain (ETC) complex I, resulting in increased levels of reactive oxygen species (ROS) in the hippocampus of rats. Specifically, Hcy suppressed Ndufa1 expression, which is essential for complex I assembly and activation, by interfering with its transcription factor Creb1. Moreover, we found that Hcy induced neurodegeneration-like pathological changes in mitochondria in the brain via the inhibition of the NAD+/Sirt1 pathway, including defects in mitochondrial morphology, mitochondrial biogenesis, and mitophagy, ultimately leading to impairments in synapses and cognition, all of which were reversed by Ndufa1 upregulation. Thus, Ndufa1 is a key molecular switch of Hcy-induced mitochondrial damage, and appropriately targeting Ndufa1 or NAD+ replenishment may serve as a novel therapeutic strategy for Hcy-induced neurodegeneration and cognitive impairment.

DOI: https://doi.org/10.1038/s41419-025-07834-3
Int J Mol Med. 2025 Sep;pii: 139. [Epub ahead of print]56(3):

Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).

Yunlong Sun, Kaifang Wei, Xudong Liao, Jian'an Wang, Li'na Gao, Bo Pang.

  Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and neuroinflammation, with microglial dysfunction emerging as a central driver of pathogenesis. Microglia, the central nervous system‑resident immune cells, exhibit dual pro‑inflammatory and anti‑inflammatory phenotypes, dynamically regulated by lipid metabolic reprogramming. Chronic activation of M1 microglia exacerbates neuronal damage, while M2 microglia promote tissue repair via phagocytic clearance and neurotrophic factor secretion. Lipid dysregulation‑marked by ceramide accumulation, cholesterol esterification defects and oxidized lipid‑driven neuroinflammation‑critically modulates microglial polarization. Mechanistic studies reveal that mitochondrial dysfunction, lysosomal stress and ferroptosis intersect with lipid metabolic pathways to amplify neurotoxicity. Therapeutic strategies targeting lipid homeostasis, such as TREM2 agonism, demonstrate efficacy in preclinical models by restoring microglial function and mitigating pathology. This review synthesizes emerging evidence linking microglial lipid metabolism to NDD progression, highlighting novel biomarkers and therapeutic avenues to disrupt the lipid‑neuroinflammation axis in neurodegeneration.

Keywords:  ferroptosis; lipid metabolism; microglia; neurodegeneration

DOI:  https://doi.org/10.3892/ijmm.2025.5580
Mol Genet Metab. 2025 Jun 28. pii: S1096-7192(25)00175-1. [Epub ahead of print]145(4): 109184

A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions.

Olivia Sniezek Carney, Kodi Harris, Madison Santizo, Valeria Silva, Jhanay Davis, Kyuna Lee, Sharada Vishwanath, Anne Hamacher-Brady, Hilary J Vernon.

  Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodeling are mediated by a coordinated set of enzymes, and disruptions in this pathway are increasingly recognized as causes of inherited mitochondrial diseases. This review provides a comprehensive overview of the genetic disorders associated with defects in cardiolipin metabolism, highlighting genetic and molecular characteristics, clinical manifestations, and available models with which to study these diseases. We examine the roles of key genes involved in cardiolipin biosynthesis (PGS1, CRLS1) and remodeling (TAZ, AGK, among others), and describe how pathogenic variants disrupt mitochondrial function. The prototypical disorder, Barth syndrome, is discussed in depth alongside recently identified conditions linked to defects in related enzymes.

Keywords:  Barth syndrome; Cardiolipin; Lipid biosynthesis; Mitochondrial disease

DOI:  https://doi.org/10.1016/j.ymgme.2025.109184
Cell Rep. 2025 Jul 10. pii: S2211-1247(25)00732-6. [Epub ahead of print]44(7): 115961

Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4.

Roxan A Stephenson, Jordy Sepulveda, Kory R Johnson, Adrian Lita, Jaanam Gopalakrishnan, Dominic J Acri, Alexandra Beilina, Linling Cheng, Linda G Yang, Jessica T Root, Michael E Ward, Christian Combs, William C Skarnes, Mark R Cookson, Han-Yu Shih, Mioara Larion, G William Rebeck, Priyanka S Narayan.

  Changes to cellular lipids accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in the cell state. In fact, both triglyceride biosynthesis and catabolism are critical for the activation-induced transcription and secretion of inflammatory cytokines and chemokines, as well as changes in phagocytosis. In microglia harboring the Alzheimer's disease risk APOE4 genotype, inhibiting triglyceride biosynthesis attenuates disease-associated transcriptional states. Triglyceride biosynthesis inhibition also rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can tune microglial immune activity in response to extrinsic activation and in APOE4-associated disease.

Keywords:  APOE; Alzheimer's; CP: Neuroscience; activation; disease; iPSCs; lipid droplets; lipid metabolism; microglia; motility; neuroinflammation; triglycerides

DOI:  https://doi.org/10.1016/j.celrep.2025.115961
Sci Rep. 2025 Jul 08. 15(1): 24460

PTEN deficiency in postnatally developing Purkinje cells disrupts metabolic signaling, leading to dendritic abnormalities and sex-specific behavioral deficits.

Lindsay J Walsh, Izabella M Espinal-San Miguel, Ana V Rodriguez, Ursula M Peña, Kiley E Flynn, Will C Remillard, Siena R Brazier, Natalia I Anderson, Aidan J Clark, Tiffany A De Varona, Ileana Soto.

  Conditional deletion of the Pten gene in cerebellar Purkinje cells (PCs) results in cellular hypertrophy, neurodegeneration, and autism-like behaviors in adult mice. Here, we investigated the effects of PTEN conditional deficiency on PC dendritic development and early postnatal motor, spontaneous, and social behaviors. We found that Pten loss disrupts dendritic growth by altering mTOR signaling and reducing AMPK phosphorylation, leading to early motor deficits and sex-specific behavioral alterations. In vivo analysis revealed significant reductions in mitochondrial and lysosomal volume in developing dendrites. Notably, ex vivo treatment with AICAR (an AMPK activator) or Torin1 (an mTOR inhibitor) partially restored dendritic organelle content in Pten-deficient PCs. These findings suggest that PTEN is critical for maintaining metabolic balance during postnatal dendritic maturation, and its loss leads to structural and functional impairments in PCs that contribute to behavioral phenotypes in a sex- and age-dependent manner.

Keywords:  AICAR; AMPK; Lysosomes; Mitochondria; PTEN; Purkinje cells; Torin1; mTORC1

DOI:  https://doi.org/10.1038/s41598-025-09059-y
Exp Biol Med (Maywood). 2025 ;250 10607

Assessing the developmental effects of fentanyl and impacts on lipidomic profiling using neural stem cell models.

Cheng Wang, Jinchun Sun, Rohini Donakonda, Richard Beger, Leah E Latham, Leihong Wu, Shuliang Liu, Joseph P Hanig, Fang Liu.

  Fentanyl is a potent and short-acting opioid that is often given to pediatric patients during surgery to relieve pain and as an adjunct to anesthesia. Its effects on the developing brain are yet to be determined. In the present study, commercially available human neural stem cells (NSCs) were used to model the effects of fentanyl on the developing human brain. We determined the dose dependent effects and temporal relationships between fentanyl exposures and NSC health, viability, and differentiation. Markers of mitochondrial health [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT)] and cell death/damage [lactate dehydrogenase (LDH)] were monitored to determine the dose response effects of fentanyl on NSC viability. In addition, lipidomics analysis was conducted to investigate lipid profile changes in differentiated neural cells treated with fentanyl. Fentanyl did not cause a significant increase in LDH release, nor MTT reduction after 24-h exposure at concentrations of 0.5, 1.0, 3.0, 10, or 100 μM, for both NSCs and differentiated neural cells. Lipidomics data showed the top 15 most variable important in projection (VIP) lipid species (the higher the VIP scores, the bigger changes in treated groups vs. controls), including lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), ceramides (CER), cholesterol esters (ChEs) and sphingosine (SPH). The lipidomic data indicate that LPC (16:0), LPC (16:1), LPC (18:1), CER (d18:0_22:0), CER (d18:2_18:0), CER(d18:2_24:1) were significantly increased, and only ChE (24:5) and SPH (d18:1) were significantly decreased in the highest dose group versus control. These data indicated that fentanyl exposure (24-h) did not induce detectable cell death. However, a lipidomic analysis indicated that fentanyl may affect immature neural cell functions through modifying lipid composition and lipid metabolism. These data indicated that despite the absence of clear neurodegeneration, fentanyl may still have a negative impact on the developing brain.

Keywords:  anesthetics; development; fentanyl; lipidomic analysis; neurotoxicity

DOI:  https://doi.org/10.3389/ebm.2025.10607
Front Nutr. 2025 ;12 1635266

Nervonic acid in infant nutrition: a forward-looking approach to enhancing neurodevelopmental outcomes.

Frédéric Destaillats, Manuel Oliveira, Walter Rakitsky, Xiaoying Zhou, Leon Parker.

  Nervonic acid (24:1 n-9, NA) is a monounsaturated very long-chain fatty acid (VLCFA) that plays a fundamental role in brain development, particularly in the biosynthesis of sphingolipids and myelin sheaths. NA is present in minute amounts in human milk and despite its importance in neuronal function and cognitive development, there is currently no ingredient available for the fortification of infant nutrition products. However, recent advances in biotechnology have made it feasible to produce high NA containing oil through fermentation, presenting a significant opportunity to address this nutritional gap. This review explores the potential of NA fortification in infant nutrition products and its impact on neurodevelopment, with a specific focus on two populations: premature infants, who are at higher risk of neurodevelopmental impairments due to incomplete in utero myelination, and healthy term infants, who may experience enhanced cognitive development with improved dietary NA intake when consuming infant formula. By critically examining the scientific basis for NA supplementation, as well as the practical challenges and regulatory considerations associated with its implementation, this review aims at providing a forward-looking perspective on how this emerging ingredient could enhance infant nutrition and improve health outcomes.

Keywords:  brain development; fermentation; infant nutrition; milk-fat globule membranes; myelination; nervonic acid; premature infants; sphingolipids

DOI:  https://doi.org/10.3389/fnut.2025.1635266
Cereb Cortex. 2025 Jul 01. pii: bhaf165. [Epub ahead of print]35(7):

Mapping of neurovascular and neurometabolic couplings by multimodal optical imaging.

Peter Herman, Simon Sanggaard, Shaun D James, Adil Akif, Sandeep Kumar Mishra, Basavaraju G Sanganahalli, Justus V Verhagen, Hal Blumenfeld, Fahmeed Hyder.

  Neurovascular coupling links calcium (Ca2+)-dependent neuronal activity to cerebral blood volume changes, whereas neurometabolic coupling describes alterations of neuronal activity and glucose uptake. While mesoscale optical imaging of neurovascular coupling is prevalent, neurometabolic coupling has been explored much less. We describe a multiplexed optical system with a closed cranial window setup for longitudinal studies in Thy1-jRGECO1a mice where neuronal activity is measured with Ca2+-dependent red fluorescence, glucose uptake with bolus injections of 2NBDG with green fluorescence, and cerebral blood volume (CBV) with near-infrared spectroscopy (NIRS). Genetically encoded calcium indicators (GECIs) provide strong fluorescent signals for assessing Ca2+-dependent neuronal activity. Thy1-jRGECO1a, a novel GECI with red fluorescence emission that penetrates deeper into tissue, allows for simultaneous imaging of metabolic activity using a green-fluorescent glucose analog, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2NBDG), which is taken up like glucose and then phosphorylated. Dual-fluorescent (red, green) and NIRS recordings confirm strong neurovascular coupling during hindpaw stimuli (Ca2+-CBV; P = 0.0033, r2 = 0.91), whereas neurometabolic coupling (Ca2+-2NBDG; P < 0.001) was three times stronger during stimulation (r2 = 0.75; slope = 0.6) compared to rest (r2 = 0.49; slope = 0.23). In summary, multiplexed optical imaging can be used to reveal mechanisms of neurovascular and neurometabolic (un)couplings during ischemia, traumatic brain injury, aging, and Alzheimer's disease.

Keywords:  2NBDG; Ca2+ imaging; Thy1-jRGECO1a; aerobic glycolysis; glucose consumption; near-infrared spectroscopy

DOI:  https://doi.org/10.1093/cercor/bhaf165
Adv Sci (Weinh). 2025 Jul 08. e04175

Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.

Francesca Alves, Darius Lane, Adam Wahida, Md Jakaria, Pawel Kalinowski, Adam Southon, Abdel Ali Belaidi, Teresa Samperi-Esteve, Triet Phu Minh Nguyen, Peng Lei, Marcus Krueger, Stefan Mueller, Marcus Conrad, Puja Agarwal, Sue E Leurgans, Julie Schneider, Ashley I Bush, Scott Ayton.

  Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.

Keywords:  ATP; alzheimer's disease; bioenergetics; ferroptosis; glutathione; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1002/advs.202504175
Life Sci Alliance. 2025 Sep;pii: e202503323. [Epub ahead of print]8(9):

Loss of PLA2G4E compromises synaptic structure and cognitive outcomes in mice.

Sara Badesso, Marta Perez-Gonzalez, Sara Exposito, Maria Espelosin, Clara Cambria, Laura D'Andrea, Gabriele Imperato, Pedram Moeini, Africa Vales, Gloria Gonzalez-Aseguinolaza, Nico Mitro, Flavia Antonucci, Eduardo D Martín, Elena Marcello, Mar Cuadrado-Tejedor, Ana Garcia-Osta.

Given its potential role in supporting cognitive resilience, PLA2G4E has emerged as a compelling therapeutic target in the context of Alzheimer's disease (AD). However, its physiological functions in the central nervous system remain largely unexplored. In this study, we demonstrate that Pla2g4e expression peaks during early postnatal brain development, coinciding with the rapid formation of synapses. Loss-of-function experiments in primary neuronal cultures revealed that Pla2g4e expression is essential for proper dendritic development and neuronal maturation. In constitutive Pla2g4e knockout mice, we observed significant disruptions in the developmental profiles of cortical synaptic plasticity markers, accompanied by impairments in memory-related behaviors. Notably, the adeno-associated virus-mediated overexpression of PLA2G4E rescued memory deficits, highlighting its functional relevance in cognitive processes. Furthermore, selective deletion of Pla2g4e in excitatory neurons of the adult brain resulted in moderate memory impairments in aged animals, suggesting an ongoing role in synaptic maintenance. Together, these findings establish PLA2G4E as a key regulator of dendritic architecture, synaptic function, and cognitive performance, and highlight its potential as a gene therapy target for neurodegenerative diseases characterized by synaptic dysfunction.

DOI: https://doi.org/10.26508/lsa.202503323