bims-medebr 2026-06-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–06–14
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Targeting Brain Cholesterol Homeostasis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.
Sex differences in brain glucose metabolism and Alzheimer's disease risk and progression.
The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.
Neurovascular coupling and energy substrate delivery in Alzheimer's disease.
Starved synapses: Gut microbiome dysbiosis and its role in Alzheimer's glucose impairment.
A Polarity-Sensitive Lipid Droplet Probe Reveals Aβ Species-Dependent Lipid Droplet Remodeling in Microglia.
Metformin Modulates Systemic Lipid Remodeling after Traumatic Brain Injury.
Environmental toxins, PFAS exposure, and brain metabolism: A new angle in Alzheimer's disease pathophysiology.
DHDDS-related juvenile parkinsonism is caused by impaired lipid metabolism, glycosylation, and mitochondrial dysfunction, which can be rescued by NAD⁺ treatment.
SREBPs in Metabolic Reprogramming and Disease: Mechanisms and Therapeutic Potential.
β-Lapachone-Induced Oxidative Stress Causes PARP-Dependent NAD+-Depletion that Affects the Energy Metabolism of Cultured Primary Rat Astrocytes.
Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.
A‑type potassium channels mediate the inhibitory effect of β‑hydroxybutyrate on CA1 pyramidal neurons in an immature mouse model of kainic acid‑induced status epilepticus.
Irisin promotes selective changes in hippocampal mitochondrial metabolism in mice.
Five-year change in brain metabolism across the spectrum of cognitive impairment in older adults: a quantitative MRI study.
Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.
Multi-omics reveal phosphatidic acid phosphatases modify Niemann-Pick type C disease severity.
Transcriptional correlates of structure-function coupling plasticity in trigeminal neuralgia: unveiling the synaptic and metabolic associations.
FABP3 Aggravates Cerebral Ischemia-Reperfusion Injury by Promoting Mitochondrial Lipid Accumulation and Enhancing BAX-Dependent Apoptosis.
Time-restricted feeding rejuvenates cerebrovascular function and preserves cognition during aging.
A new mechanism underlying mitochondrial dysfunction in schizophrenia - attenuated mRNA transport of the complex I subunit NDUFV2 by its pseudogene NDUFV2P1.
Tracking Gene Expression of Single Mitochondria in Live Neurons Using Nanotweezers.

J Neurochem. 2026 Jun;170(6): e70492

Targeting Brain Cholesterol Homeostasis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.

Myuri Ruthirakuhan, Ameer Y Taha, Walter Swardfager.

Cholesterol is a fundamental component of the central nervous system, supporting myelin integrity, synaptic structure, membrane organization, and neuronal signaling. Because the brain is largely isolated from peripheral cholesterol pools, tight regulation of brain cholesterol homeostasis is required to sustain neuronal and glial function across the lifespan. Growing evidence indicates that disruption of this balance is not merely a downstream consequence of neurodegeneration, but an upstream contributor to Alzheimer's disease (AD) pathogenesis. Altered brain cholesterol homeostasis has been linked to amyloidogenic processing, tau pathology, neuroinflammation, synaptic dysfunction, and cerebrovascular injury. This review synthesizes current evidence showing how multiple converging stressors, including peripheral hypercholesterolemia, neurodegeneration, oxidative stress, and inflammatory signaling, perturb brain cholesterol regulation. These drivers disrupt the coordinated processes of cholesterol synthesis, metabolism, and transport, shifting the system from tightly regulated sterol flux toward impaired clearance, abnormal lipid distribution, and membrane instability. Such disturbances remodel membrane lipid composition, alter lipid raft organization, and impair glial-neuronal lipid coupling, thereby accelerating amyloid-β production, tau-related vulnerability, innate immune activation, and neurovascular dysfunction. Finally, we provide an overview of therapeutic strategies aimed at restoring cholesterol balance, and highlight the potential of integrated, multi-target strategies to complement amyloid- and tau-directed therapies. By clarifying how disruptions in brain cholesterol homeostasis link systemic and central stressors to AD pathology, this review identifies cholesterol regulation as a critical, upstream axis for therapeutic intervention and disease prevention.

DOI: https://doi.org/10.1111/jnc.70492
Alzheimers Dement. 2026 Jun;22(6): e71491

Sex differences in brain glucose metabolism and Alzheimer's disease risk and progression.

Marjan Ramezan, Aphrodite Demetriou, Sara Nicole Burke, Ivan Nalvarte, Andrew C Shin.

  Sex differences are increasingly recognized as central to the biology of Alzheimer's disease (AD), yet the mechanisms through which they shape brain metabolism and disease vulnerability remain incompletely understood. Brain glucose hypometabolism is a core hallmark of AD and emerges decades before clinical decline, but accumulating evidence indicates that its causes, timing, and functional consequences differ between women and men. In this review, we synthesize findings from neuroimaging, molecular, and cellular studies to examine how sex-dependent regulation of glucose transport, glycolysis, and mitochondrial function interacts with aging and AD pathology. We highlight reinforcing evidence for a steeper and more pathology-linked decline in mitochondrial glucose metabolism in females, particularly in the context of menopause and apolipoprotein E (APOE) ε4 genotype. We identify major knowledge gaps at the level of cell type, brain region, and disease stage, and outline priorities for sex-informed, mechanistically anchored research to enable metabolic-precision interventions for AD risk and progression.

Keywords:  aging; bioenergetics; hypometabolism; mitochondrial functions; sex hormones

DOI:  https://doi.org/10.1002/alz.71491
Int J Mol Sci. 2026 May 29. pii: 4932. [Epub ahead of print]27(11):

The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.

Yoo Been Chang, James D Baleja.

  The ketogenic diet, a high-fat and low-carbohydrate diet, has potential therapeutic effects on various neurological and psychiatric disorders. The diet shifts the body's energy production in the form of adenosine triphosphate from using glucose to fats. The increased fatty acid β-oxidation results in the production of ketone bodies. This metabolic adaptation changes cellular bioenergetics, especially in the brain, which is highly reliant on energy metabolism. Schizophrenia, a psychotic disorder, and bipolar disorder, a mood disorder, are distinct psychiatric illnesses that can both involve disturbances in mood, cognition, and perception. These disturbances differ in prominence and clinical significance between the two conditions. Although the underlying mechanisms behind each disorder vary, they share some common pathophysiology, such as imbalances in the neurotransmitter system, mitochondrial dysfunction, and oxidative stress. Alzheimer's disease, a neurodegenerative disorder marked by progressive cognitive decline, shares similar cellular disruptions, along with additional pathological features such as neuroinflammation and neuronal death. Recent studies suggest that the ketogenic diet may exert therapeutic effects by modulating underlying biochemical pathways. Its ability to reduce oxidative stress, improve mitochondrial function, and stabilize neurotransmitter balance may help alleviate symptoms and potentially slow disease progression.

Keywords:  Alzheimer’s disease; bipolar disorder; brain energy metabolism; ketogenic diet; mitochondrial dysfunction; neurotransmitter dysregulation; oxidative stress; schizophrenia

DOI:  https://doi.org/10.3390/ijms27114932
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00029-2. [Epub ahead of print]186 317-338

Neurovascular coupling and energy substrate delivery in Alzheimer's disease.

Shivam Malviya, Debasmita Saha, Anagha Kamble, Divya Ramesh Singh, Sivaraj Mohana Sundaram, Vasudharani Devanathan.

  The brain has exceptionally high metabolic demands and depends on a continuous supply of oxygen and glucose to maintain neuronal activity and cognitive function. Despite accounting for only about 2 % of body weight, it consumes more than 20 % of the body's energy. This demand is met through tightly regulated cerebral blood flow mediated by neurovascular coupling (NVC), a process that links neuronal activity with local vascular responses. The cellular components responsible for this regulation including neurons, astrocytes, endothelial cells, pericytes, and vascular smooth muscle cells form the neurovascular unit (NVU), which maintains blood brain barrier (BBB) integrity, metabolic homeostasis, and efficient substrate delivery. Increasing evidence suggests that disruption of neurovascular and metabolic regulation is an early and critical contributor to Alzheimer's disease (AD). Impairment of NVU function leads to reduced cerebral blood flow, endothelial dysfunction, pericyte loss, and breakdown of the BBB. These vascular changes compromise the delivery of oxygen and glucose, resulting in cerebral hypometabolism that often precedes classical pathological hallmarks such as amyloid-β plaques and tau neurofibrillary tangles. Alterations in glucose transport across the BBB, particularly reduced expression of the GLUT1 transporter, further exacerbate neuronal energy deficits. Disturbances in lactate metabolism and mitochondrial dysfunction also contribute to oxidative stress and progressive neurodegeneration. Understanding the interaction between neurovascular dysfunction, impaired brain metabolism, and AD pathology provides important insight into disease progression. Therapeutic strategies aimed at restoring vascular function, improving metabolic substrate delivery, and enhancing neuronal energy metabolism may offer promising avenues for early intervention in AD.

Keywords:  Blood brain barrier; Brain glucose metabolism; Cerebral blood flow; Cerebral hypometabolism; GLUT1 transporter; Neurovascular coupling; Neurovascular unit

DOI:  https://doi.org/10.1016/bs.irn.2026.05.001
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00010-3. [Epub ahead of print]186 241-264

Starved synapses: Gut microbiome dysbiosis and its role in Alzheimer's glucose impairment.

Riddhi Upadhyay, Sneha Santhosh, R Malathi, P Saravana Kumari, S Vijayanand, Murugan Sevanan.

  Alzheimer's disease (AD) is increasingly recognised as a multifactorial disorder driven by metabolic, microbial, and neuroinflammatory imbalances. The study of the research results proposes that gut dysbiosis and impaired brain glucose metabolism are closely interrelated through the gut-brain metabolism axis. Changes in the intestinal microbiome may disrupt insulin sensitivity, cause systemic inflammation, and disrupt the blood-brain barrier, worsening neuronal glucose deficits and facilitating amyloid-β (Aβ) aggregation and tau phosphorylation. Alongside, neurodegenerative cascades are further enhanced by neuronal metabolic reprogramming, characterised by decreased glucose uptake, dysfunctional glycolytic enzymes, and oxidative stress. Short-chain fatty acids (SCFAs) are mainly butyrate, which have a neuroprotective effect in regulating inflammation and gut integrity, and dysbiosis causes increased pro-inflammatory cytokines and endotoxin leakage. This two-way communication network provides new therapeutic opportunities, such as probiotics, prebiotics, nutritional control, and metabolic reprogramming interventions, to regain homeostasis and prevent the advancement of AD.

Keywords:  Astrocyte; Blood–Brain Barrier (BBB) Transport; Glucose Metabolism; Gut–Brain Axis Dysregulation; Lactate Metabolism; Metabolic Crosstalk

DOI:  https://doi.org/10.1016/bs.irn.2026.01.010
ACS Sens. 2026 Jun 09.

A Polarity-Sensitive Lipid Droplet Probe Reveals Aβ Species-Dependent Lipid Droplet Remodeling in Microglia.

Panyi Hu, Shuo Guo, Youxiang Ren, Rui Zhao, Liping Su, Jiahan Cheng, Xiaohe Tian.

  Microglial lipid metabolic alterations are increasingly implicated in Alzheimer's disease (AD), yet the specific β-amyloid (Aβ) species involved in lipid droplet (LD) remodeling remain unclear. Precise visualization of LD morphology in complex biological systems is limited by the availability of selective and photostable probes. Herein, we report a polarity-sensitive LD probe, BODIPY-LD, constructed with a donor-π-acceptor-π-donor (D-π-A-π-D) framework that enables hydrophobic targeting and intramolecular charge transfer (ICT)-based fluorescence activation in low-polarity environments. The probe allows high-contrast visualization and quantitative assessment of LD morphology in cells and brain tissues. Using BODIPY-LD, we observed increased LD burden in hippocampal microglia of APP/PS1 mice and systematically compared the effects of different Aβ25-35 assembly states on LD accumulation in BV2 microglia. Among monomeric, oligomeric, and fibrillar Aβ25-35 forms, the monomer-treated BV2 cells showed the most pronounced LD enrichment under our experimental conditions. This LD-rich phenotype was associated with reduced phagocytic capacity and was partially reversible upon inhibition of LD synthesis using the long-chain acyl-CoA synthetases (ACSL) inhibitor Triacsin C. Together, these findings suggest that monomeric Aβ25-35 is associated with an LD-rich microglial phenotype and impaired phagocytic function in vitro model. Beyond this biological observation, BODIPY-LD provides a useful tool for studying lipid remodeling in neuroinflammatory contexts.

Keywords:  Alzheimer's disease; Aβ species; fluorescent probe; lipid droplet; microglial metabolism

DOI:  https://doi.org/10.1021/acssensors.6c01055
Res Sq. 2026 Jun 04. pii: rs.3.rs-9583079. [Epub ahead of print]

Metformin Modulates Systemic Lipid Remodeling after Traumatic Brain Injury.

Aaron M Gusdon, Sung-Min Cho, Hua Chen, Farid Radmanesh, Xuefang Ren, Pramod Dash, Jae-Hyek Choi, R Madelaine Paredes.

Background Traumatic brain injury (TBI) induces systemic metabolic disturbances, particularly affecting lipid metabolism, which may contribute to secondary injury. Metformin has pleiotropic effects on mitochondrial function and lipid homeostasis, but its impact on the circulating lipidome after TBI remains poorly characterized. Methods We performed plasma lipidomic profiling in a porcine TBI model with metformin or control pretreatment. Paired pre- and post-TBI samples from 20 swine enabled within-subject comparisons. Lipidomic data were analyzed using complementary univariate and multivariate approaches, including paired differential abundance testing, principal component analysis (PCA), unsupervised hierarchical clustering with permutation-based cluster purity assessment, and sparse partial least squares discriminant analysis (sPLS-DA). Results Unsupervised analyses demonstrated coordinated lipidomic remodeling following TBI, characterized by enrichment of triglycerides and depletion of phosphatidylinositols. Metformin treatment had minimal effects on baseline metabolic profiles, with only subtle multivariate separation and near-chance classification performance. In contrast, post-TBI samples showed clearer treatment-associated differences, including improved separation in PCA, hierarchical clustering, and sPLS-DA models. These differences were driven by coordinated changes across multiple lipid classes rather than large shifts in individual metabolites. Notably, metformin treatment was associated with altered post-TBI patterns of triglycerides containing polyunsaturated fatty acids, phospholipids, lysophospholipids, and cholesteryl esters, suggesting modulation of injury-associated lipid remodeling. Conclusions Metformin exerts modest effects on baseline lipid metabolism but is associated with coordinated alterations in the systemic lipidomic response following TBI. These findings support a context-dependent role for metformin as a modulator of post-injury metabolic remodeling and highlight lipid pathways as potential targets for therapeutic intervention after TBI.

DOI: https://doi.org/10.21203/rs.3.rs-9583079/v1
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00011-5. [Epub ahead of print]186 107-144

Environmental toxins, PFAS exposure, and brain metabolism: A new angle in Alzheimer's disease pathophysiology.

Vedika Jain, Sharda Bharti.

  Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complicated cause and effect, usually associated with amyloid-β plaques, tau pathology, and neuroinflammation. Recent research indicates that changes in brain energy metabolism play a crucial role in the progression of AD. Additionally, persistent environmental toxins, particularly per- and polyfluoroalkyl substances (PFAS), have attracted considerable attention due to their widespread occurrence, ability to accumulate in living organisms, and neurotoxic effects. This chapter explores the connection between PFAS exposure and metabolic dysfunction in the brain as a potential new factor in the etiology of Alzheimer's disease. This study explored the potential impacts of PFAS on insulin signaling, lipid homeostasis, glucose metabolism, mitochondrial dynamics, and brain energy supply. The epidemiological associations between PFAS exposure and cognitive impairment are also examined, along with the mechanisms underlying oxidative stress, neuroinflammation, and dysregulation of metabolic systems. Finally, prevention, management, therapeutic approaches, and the research gap in PFAS-induced neurotoxicity are explored. Findings from this study emphasize the need to incorporate environmental toxicology into the Alzheimer's disease metabolic model for the sake of future treatment and preventive efforts.

Keywords:  Alzheimer’s disease; Brain metabolism; Environmental toxicology; Neurotoxicity; PFAS

DOI:  https://doi.org/10.1016/bs.irn.2026.01.011
medRxiv. 2026 Jun 05. pii: 2026.05.28.26354198. [Epub ahead of print]

DHDDS-related juvenile parkinsonism is caused by impaired lipid metabolism, glycosylation, and mitochondrial dysfunction, which can be rescued by NAD⁺ treatment.

I J J Muffels, K A Kantautas, G MacDonald, K Garapati, R R Pasupuleti, R J Tinker, R Shah, M A Thevandavakkam, J Donnelly, R Hrstka, D Smith, J Van Klinken, F Vaz, A Pandey, E O Perlstein, T Kozicz, E Morava.

Background: Mono-allelic Dehydrodolichyl Diphosphate Synthase ( DHDDS) variants are associated with juvenile Parkinsonism, developmental delay and seizures. Symptoms are progressive, and various mechanisms, such as defective glycosylation, lysosomal dysfunction and cholesterol accumulation have been hypothesized to underlie disease symptoms. There is no treatment for DHDDS-related disease.
Methods: Patient-derived cortical forebrain organoids were created to elucidate disease mechanisms and evaluate potential treatments. In these neuronal models, glycosylation, lipidomics, proteomics, cholesterol/ganglioside accumulation, mitochondrial function and electrophysiological activity were assessed. Finally, we investigated the effects of nicotinamide mononucleotide (NMN), identified through a yeast-based drug screen, in neuronal cell models and in six patients in an off-label, N-of-1, observational series.
Results: DHDDS-patient derived organoids showed visual signs of degeneration after four months of culturing. This was accompanied by significant cholesterol accumulation in astrocytes, decreased mitochondrial respiration and loss of deep-layer neurons. In addition, we identified glycosylation abnormalities, showing for the first time that glycosylation in human tissue is affected by monoallelic DHDDS variants. Proteomic analysis revealed altered protein expression of proteins involved in lipid metabolism, cytoskeletal organization and neuronal development. We found that oral Nicotinamide Mononucleotide supplementation led to significant improvement in mitochondrial respiration and electrophysiological parameters in organoids, concurring with clinical improvements in all of the treated patients, particularly regarding their ataxia and tremor.
Conclusion: Our findings reveal a progressive phenotype in DHDDS-patient-derived brain organoids, with mitochondrial dysfunction and astrocyte-specific metabolic alterations contributing to disease pathology. Notably, NMN treatment led to clinical improvements in patients with heterozygous DHDDS variants, highlighting its potential as a therapeutic strategy.

DOI: https://doi.org/10.64898/2026.05.28.26354198
FASEB J. 2026 Jun 30. 40(12): e72037

SREBPs in Metabolic Reprogramming and Disease: Mechanisms and Therapeutic Potential.

Xinhong Zou, Yingyu Li, Mu Yang, Lei Liu, Rui Wu, Guoli Cui, Junfei Dai.

  Sterol regulatory element-binding proteins (SREBPs) are key transcription factors belonging to the basic helix-loop-helix leucine zipper (bHLH-Zip) family. They play central roles in coordinating cellular lipid metabolic signaling and maintaining metabolic homeostasis. This review systematically summarizes the origin, classification, structural characteristics, and activation mechanisms of SREBPs mediated by the INSIG-SCAP-SREBP complex. Building on this, we further outline the lipid metabolic programs regulated by SREBPs, with a focus on their roles in de novo lipogenesis, triglyceride accumulation, cholesterol metabolism, and membrane remodeling. In addition, we provide a cross-disease overview of SREBP-driven metabolic reprogramming, highlighting its involvement in inflammation amplification, immune metabolic imbalance, disruption of cellular homeostasis, and malignant progression. Based on current advances, we also summarize emerging small-molecule modulators targeting SREBP signaling and their potential therapeutic value. Furthermore, we discuss key challenges in current research, including functional heterogeneity, context-dependent regulation, organismal and cell-type specificity, as well as barriers to clinical translation. Overall, SREBPs are not only central regulators of lipid metabolism but also pivotal hubs linking metabolic remodeling to disease progression. A deeper understanding of their mechanisms and targeted interventions is expected to provide new insights for therapeutic strategies against metabolic diseases.

Keywords:  SREBPs; cholesterol homeostasis; de novo lipogenesis; lipid metabolism; metabolic reprogramming; therapeutic targets

DOI:  https://doi.org/10.1096/fj.202600280RR
Neurochem Res. 2026 Jun 12. pii: 192. [Epub ahead of print]51(3):

β-Lapachone-Induced Oxidative Stress Causes PARP-Dependent NAD+-Depletion that Affects the Energy Metabolism of Cultured Primary Rat Astrocytes.

Johanna Elisabeth Willker, Ralf Dringen.

  Oxidative stress has been connected with many brain pathologies. As brain astrocytes have a strong antioxidative potential, we have investigated the consequences of β-lapachone-induced oxidative stress on the cell metabolism of cultured astrocytes by determining the cellular levels of important components of the cellular redox and energy metabolism. β-Lapachone exposure induced a rapid oxidation of cellular NADH and NADPH followed by a time- and concentration-dependent loss in the total cellular NADx content and an increase in the total cellular NADPx content, while the cell viability was not compromised. In addition, the treated cells were partially depleted of ATP and lost their ability to upregulate glycolytic lactate production after exposure to the respiratory chain inhibitor antimycin A. All these consequences were prevented in the presence of ES936 which inhibits the NQO1-mediated reduction of β-lapachone. Inhibition of poly(ADP-ribose) polymerases (PARPs) by PJ34 or AZD-2461 did not affect the strong cellular accumulation of glutathione disulfide, but significantly lowered the oxidative stress-induced loss in the cellular NADx and ATP contents, maintained the ability of the cells to upregulate glycolytic lactate production during incubation with antimycin A, and doubled the increase in the cellular NADPx content. After removal of the β-lapachone-induced oxidative stress, astrocytes were able to restore their initial cellular content of NADx in the presence of the NAD+ precursor nicotinamide. This restoration was accompanied by the reestablishment of the ability to upregulate glycolytic lactate production during antimycin A exposure. The results obtained show that oxidative stress has severe consequences on various fundamental metabolic parameters of astrocytes, but also demonstrate the high potential of these cells to recover after severe oxidative stress.

Keywords:  ATP; Astrocytes; Glutathione; Nicotinamide coenzymes; Oxidative stress; PARP; β-Lapachone

DOI:  https://doi.org/10.1007/s11064-026-04814-7
Metab Brain Dis. 2026 Jun 10. pii: 132. [Epub ahead of print]41(1):

Mitochondrial enzyme dysfunction in Alzheimer's disease: a systematic review of human metabolic evidence.

Mahsa Asadi Anar, Mohammad Amin Fathollahi, Fereshteh Zare, Zahra Farrokhi, Elham Habibzadeh, Saina Hasany, Majid Mirmazloumi, Melika Arab Bafrani, Fatemeh Abedian Kenari, Marjan Falahati, Kamyar Khorsand, Amirali Zakavi, Yasaman Asadollah Salmanpour, Elham Yadegarifard, Farbod Khosravi, Parsa Goudarzi.

  Alzheimer's disease (AD) is characterized by progressive cognitive decline accompanied by profound disturbances in cerebral energy metabolism. Mitochondrial dysfunction has long been implicated in AD pathophysiology; however, the specific contribution of mitochondrial enzymes in human disease remains fragmented across heterogeneous studies. Enzymes regulating carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, and redox balance represent key metabolic control points whose dysfunction may contribute to neuronal vulnerability. To systematically synthesize human evidence on mitochondrial enzyme alterations in Alzheimer's disease and to evaluate the feasibility of quantitative meta-analysis based on current reporting practices. A systematic literature search was conducted in PubMed, Scopus, and Web of Science from database inception through January 2026 in accordance with PRISMA 2020 guidelines. Studies were included if they investigated mitochondrial enzymes in human postmortem brain tissue, human-derived cellular models, or peripheral biospecimens. Risk of bias was assessed using the ROBINS-I tool. The feasibility of meta-analysis was evaluated based on the availability and comparability of group-level summary statistics. Fifteen studies met the eligibility criteria and were included in the final synthesis. Mitochondrial enzymes involved in carbon entry into the tricarboxylic acid cycle, oxidative phosphorylation, redox regulation, and neurotransmitter-linked mitochondrial metabolism were the most frequently investigated targets. Direct enzyme-activity evidence most consistently implicated selected metabolic control points, particularly PDHC and αKGDHC, whereas additional studies supported mitochondrial impairment through protein or post-translational modification changes, respiratory dysfunction, redox alterations, or RNA-regulatory mechanisms. Quantitative meta-analysis was not feasible due to heterogeneous assay methodologies, variable normalization strategies, and inconsistent reporting of group-level summary statistics. Human evidence consistently implicates mitochondrial enzyme dysfunction as a central metabolic feature of Alzheimer's disease. However, progress toward cumulative quantitative synthesis remains limited by methodological heterogeneity and incomplete reporting of enzyme activity outcomes. Standardized measurement and reporting of mitochondrial enzyme alterations will be essential to advance mechanistic understanding and enable future meta-analytic integration.

Keywords:  Alzheimer’s disease; Mitochondrial enzymes; Neurodegeneration; Oxidative phosphorylation; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1007/s11011-026-01895-9
Epilepsy Res. 2026 Jun 01. pii: S0920-1211(26)00111-7. [Epub ahead of print]226 107841

A‑type potassium channels mediate the inhibitory effect of β‑hydroxybutyrate on CA1 pyramidal neurons in an immature mouse model of kainic acid‑induced status epilepticus.

Guoli Zhang, Xiao-Ran Wang, Baoqi Su, Tonglaga Li, Haichun Liu, Xiangping Xu.

   BACKGROUND: The ketogenic diet (KD) is an established metabolic therapy for drug-resistant epilepsy, particularly in pediatric populations. However, the direct electrophysiological effects of its primary ketone body, β-hydroxybutyrate (BHB), on neuronal excitability in the developing brain during status epilepticus remain incompletely understood. This study investigated whether BHB suppresses hippocampal CA1 neuronal excitability in an immature mouse model of status epilepticus and elucidated the underlying ion channel mechanisms.
METHODS: Following kainic acid (KA)-induced status epilepticus in immature mice, whole-cell patch-clamp recordings were performed on hippocampal CA1 pyramidal neurons to assess resting membrane potential, action potential firing, and potassium currents, including total (IK), delayed rectifier (IKr), and A-type (IKA) currents.
RESULTS: Bath application of 3 mM BHB for 10 min significantly suppressed firing rates in both control and epileptic neurons, with a more pronounced hyperpolarizing effect on resting membrane potential in epileptic neurons. The lower concentration (0.3 mM) of BHB was ineffective. BHB (3 mM) significantly enhanced IKA in both control and epileptic neurons. In the continuous presence of 1 μM 4-AP, a selective IKA blocker, the BHB-induced IKA enhancement and the suppression of neuronal firing were completely abolished in both groups.
CONCLUSIONS: BHB suppresses hippocampal CA1 neuronal excitability in a concentration-dependent manner through selective enhancement of IKA, with enhanced efficacy in the epileptic state. These findings identify IKA as a critical molecular target for BHB-mediated excitability control and provide new insights into the therapeutic mechanisms of ketogenic diet therapy in pediatric epilepsy.

Keywords:  A-typepotassium current; Epilepsy; Hippocampal CA1 neurons; Ketogenic diet; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.eplepsyres.2026.107841
Biochem Biophys Rep. 2026 Jun;46 102657

Irisin promotes selective changes in hippocampal mitochondrial metabolism in mice.

Ariene S Fonseca, Marina S Chichierchio, Mariana G Chauvet, Guilherme B de Freitas, Andréa Tosta, Tiago Ferreira de Lima, Marcos A Formiga-Jr, Felipe C Ribeiro, Sergio T Ferreira, Fernanda G De Felice, Juliana Camacho-Pereira, Mychael V Lourenco.

  Irisin, an exercise-induced hormone, exerts neuroprotective actions in neurological disease models, yet its effects on brain mitochondrial metabolism remain unclear. Here, we examined how irisin influences mitochondrial function and dynamics in the mouse hippocampus. Acute irisin exposure boosted ATP-coupled oxygen consumption without altering mitochondrial content or dynamics-related proteins. Furthermore, chronic irisin administration in vivo decreased hippocampal Opa1 and Drp1 levels, two key regulators of mitochondrial remodeling. These findings uncover selective actions of irisin on hippocampal mitochondrial homeostasis and identify prolonged irisin exposure as a potential regulator of mitochondrial dynamics in the brain.

Keywords:  FNDC5/Irisin; Hippocampus; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.bbrep.2026.102657
Alzheimers Dement. 2026 Jun;22(6): e71561

Five-year change in brain metabolism across the spectrum of cognitive impairment in older adults: a quantitative MRI study.

Jiani Wu, Kumiko Oishi, Anja Soldan, Corinne Pettigrew, Zixuan Lin, Yuxin Zhu, Dengrong Jiang, Xin Li, Yifan Gou, Abhay Moghekar, Peiying Liu, Arnold Bakker, Kenichi Oishi, Marilyn Albert, Hanzhang Lu.

   INTRODUCTION: It is desirable to measure brain metabolism without needing ionizing radiation and elucidate its time trajectory. This study employed a positron emission tomography -validated, non-invasive magnetic resonance imaging (MRI) technique to characterize longitudinal changes in cerebral metabolic rate of oxygen (CMRO2) in both cognitively normal and impaired older adults.
METHODS: Participants received serial MRI-based CMRO2 scans between 2015 and 2025. Levels of AD pathology were measured in cerebrospinal fluid and plasma at the initial MRI.
RESULTS: At the initial visit, participants with MCI/dementia had lower CMRO2 than normal participants. In the longitudinal analyses, CMRO2 decreased over time in those who were cognitively impaired but remained unchanged in normals. Among normal participants, higher initial levels of total tau and phosphorylated tau at threonine 181 were associated with an increase in CMRO2 during follow-up, especially in amyloid-positive individuals.
DISCUSSION: Aside from the well-known metabolic slowdown in the later phases of AD, the brain exhibits tau-dependent hypermetabolism during the preclinical stage.

Keywords:  Alzheimer's disease; aging; brain metabolism; cerebral metabolic rate of oxygen (CMRO2); magnetic resonance imaging (MRI); tau

DOI:  https://doi.org/10.1002/alz.71561
Neuroscience. 2026 Jun 12. pii: S0306-4522(26)00386-6. [Epub ahead of print]

Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.

Delia Maciel Mendoza-Camacho, Hugo Alejandro Espinoza-Gutiérrez, Juan Manuel Viveros-Paredes, Mario Eduardo Flores-Soto, Aldo Rafael Tejeda-Martínez.

  Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid 2-Arachidonoylglycerol (2-AG) while simultaneously contributing to the generation of arachidonic acid and pro-inflammatory eicosanoids. Pharmacological or genetic inhibition of MAGL increases 2-AG levels and concurrently reduces the biosynthesis of pro-inflammatory lipid mediators, thereby modulating microglial activation, astrocytic responses, and neuronal excitotoxicity. Preclinical studies in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis consistently demonstrate that MAGL blockade attenuates neuroinflammation, preserves synaptic and neuronal integrity, improves motor and cognitive function, and, in some cases, delays disease progression. Although clinical evidence remains limited, the available data position MAGL as a metabolic convergence point between inflammation and neurodegeneration, suggesting that its modulation may represent a therapeutic strategy with disease-modifying potential.

Keywords:  Alzheimer’s disease; Endoc annabinoid system; Lateral Amyotrophic sclerosis; MAGL inhibition; Multiple sclerosis; Neuro degenerative diseases; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.neuroscience.2026.06.011
iScience. 2026 Jun 19. 29(6): 116121

Multi-omics reveal phosphatidic acid phosphatases modify Niemann-Pick type C disease severity.

Andrew B Munkacsi, Gabriella E Conway, Keri Multerer, Michael D Jackson, Lauren Csaki, Tamayanthi Rajakumar, Jeffrey P Sheridan, Eliatan Niktab, Wuh-Liang Hwu, Yin-Hsiu Chien, Mark Walterfang, Cintya Del Rio Hernandez, Robin B Chan, Bowen Zhou, Renu Nandakumar, Peixang Zhang, Gilbert Di Paolo, Robert A Maue, Karen Reue, Stephen L Sturley.

  Niemann-Pick type C (NP-C) disease is a fatal, neurodegenerative disorder caused by lysosomal lipid accumulation with variable symptomatic penetrance at the primary disease locus encoded by the NPC1 gene. We identified genetic modifiers of disease progression by integrating genetic, genomic, and lipidomic analyses across yeast, mice, and human patients. A yeast screen identified 45 candidate modifiers of disease severity, including phosphatidic acid hydrolase (PAH1), a key enzyme in triacylglycerol (TAG) synthesis. Lipidomic profiling of liver, cerebral cortex, and cerebellum from Npc1 -/- mice at multiple ages demonstrated that dysregulation of TAG metabolism strongly correlates with disease progression. Deletion of the murine PAH1 orthologues Lpin1 or Lpin2 in Npc1 -/- mice reduced lifespan, accelerated Purkinje cell loss, and increased hepatic lipid accumulation. In NP-C patients, two LPIN3 variants were associated with early childhood onset. These findings identify lipins as modifiers of NP-C disease and expand our understanding of lipid metabolism in neurodegeneration.

Keywords:  Disease; Genomics; Lipidomics; Model organism; Neurogenetics

DOI:  https://doi.org/10.1016/j.isci.2026.116121
J Headache Pain. 2026 Jun 06. pii: 154. [Epub ahead of print]27(1):

Transcriptional correlates of structure-function coupling plasticity in trigeminal neuralgia: unveiling the synaptic and metabolic associations.

Jian Zhang, Xujing Nie, Shuyue Fu, Yinping Lu, Tiantian Liu, Zhilin Zhang, Jinglong Wu, Xuezhi Tong, Tianyi Yan.

   BACKGROUND: Trigeminal neuralgia (TN) is characterized by severe facial pain, transitioning from peripheral vascular compression to central sensitization. However, the core central pathophysiological mechanisms-particularly how the brain structurally and functionally reorganizes to maintain pain or recover after surgical treatment (primarily microvascular decompression or percutaneous interventions)-remain to be fully elucidated.
METHODS: We employed a longitudinal multi-scale design using a graph harmonic model to quantify structure-function (S-F) coupling, a metric reflecting brain network integrity. We analysed multimodal magnetic resonance imaging data from 87 patients with TN and 42 healthy controls (HCs). Post-treatment follow-up data were acquired for 46 patients, of whom 39 had complete longitudinal paired data. We further utilised partial least squares (PLS) regression with rigorous spatial permutation testing (spin-tests) to bridge macroscopic imaging changes with microscopic transcriptomic data from the Allen Human Brain Atlas.
RESULTS: Patients exhibited significantly reduced global S-F coupling, particularly in the somatomotor and dorsal attention networks. Notably, this decoupling was negatively correlated with baseline pain severity and disease duration. Following treatment, global S-F coupling returned to levels statistically indistinguishable from healthy baselines ([Formula: see text]). Crucially, the magnitude of postoperative reorganization ([Formula: see text]S-F coupling) significantly correlated with postoperative pain reduction percentages and long-term follow-up NRS scores. This recovery extended beyond focal repair, involving extensive adaptive reorganization in the visual and default mode networks. Molecularly, disease-related decoupling was spatially associated with genes linked to neuronal energy metabolism, cellular ionic homeostasis, and neuroinflammation. Conversely, treatment-induced plasticity strongly correlated with genes modulating chemical synaptic transmission and endogenous opioid signaling.
CONCLUSIONS: TN pathophysiology is closely linked to ion channel-mediated neuronal metabolism and progressive network decoupling. Effective treatment restores homeostatic brain network coupling primarily by facilitating synaptic plasticity-based adaptive reorganization rather than merely through focal repair. This work offers a new perspective on the neural circuits underlying pain maintenance and provides potential imaging indicators for developing brain network-targeted therapeutic strategies.

Keywords:  Adaptive reorganization; Brain network; Graph harmonic model; Multimodal MRI; Structural-functional coupling; Trigeminal neuralgia

DOI:  https://doi.org/10.1186/s10194-026-02419-7
Cells. 2026 May 29. pii: 1003. [Epub ahead of print]15(11):

FABP3 Aggravates Cerebral Ischemia-Reperfusion Injury by Promoting Mitochondrial Lipid Accumulation and Enhancing BAX-Dependent Apoptosis.

Yunsi Zheng, Anqi Luo, Kohji Fukunaga, Qibing Liu, Qingyun Guo.

  We previously demonstrated that fatty acid-binding protein 3 (FABP3) is significantly upregulated in ischemic neurons, and its inhibition mitigates ischemic brain injury in mice and attenuates mitochondrial damage under rotenone-induced oxidative stress. These findings suggest a potential role for FABP3 in mitochondrial dysfunction in ischemic neurons, although the underlying mechanism remains unclear. In this study, we further investigated the role of FABP3 in mitochondrial injury and apoptosis in ischemic neurons. Our findings indicated that FABP3 deficiency significantly decreased infarct volume following middle cerebral artery occlusion/reperfusion (MCAO/R) in mice, improved cognitive and spontaneous activity deficits, and suppressed BAX activation and mitochondrial translocation, caspase-3 activation, and cytochrome c release. In HT22 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), FABP3 deficiency increased cell viability, reduced apoptosis, and alleviated the loss of mitochondrial membrane potential. Conversely, FABP3 overexpression further exacerbated mitochondrial dysfunction and apoptosis, effects that were partially reversed by the BAX inhibitor BAI1. Furthermore, FABP3 overexpression promoted abnormal mitochondrial lipid accumulation and increased lipid peroxidation. Both the mitochondria-targeted antioxidant MitoQ and the ferroptosis inhibitor Ferrostatin-1 alleviated FABP3 overexpression-induced mitochondrial damage and apoptotic signaling. Collectively, our findings suggest that FABP3 is an important promoter of cerebral ischemia-reperfusion injury. FABP3 may aggravate ischemic neuronal injury by promoting abnormal mitochondrial lipid accumulation and lipid peroxidation, thereby enhancing BAX-dependent mitochondrial apoptotic signaling. Targeting FABP3 may provide a potential therapeutic strategy for neuroprotection in ischemic stroke.

Keywords:  BAX; fatty acid-binding protein 3; ischemia/reperfusion; lipid peroxidation; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/cells15111003
Res Sq. 2026 Jun 02. pii: rs.3.rs-9520035. [Epub ahead of print]

Time-restricted feeding rejuvenates cerebrovascular function and preserves cognition during aging.

Stefano Tarantini, Madison Milan, Sharon Negri, Rakesh Rudraboina, Eva Troyano-Rodriguez, Jennifer Ihuoma, Aleksandra Kosmider, Shantipriya Awasthi, Woncheol Jung, Hassan Abushukair, Rohan Varshney, Gregory Mullen, Raghavendra Nagaraja, Niharika Uppari, Mohiuddin Ahmad, Priya Balasubramanian, Shannon Conley, Andriy Yabluchanskiy, Anna Csiszar, Zoltan Ungvari, Audrey Cleuren, Michael Rudolph, Mickael Tanter, Tae Gyu Oh, Rafael de Cabo.

Cerebromicrovascular dysfunction is a key driver of age-related cognitive decline, yet interventions targeting microvascular aging remain limited. Here, we show that time-restricted feeding (TRF) preserves cognitive function and rejuvenates cerebrovascular physiology in aged mice. TRF improves resting cerebral blood flow and neurovascular coupling while attenuating blood-brain barrier disruption, neuroinflammation, and endothelial senescence. Mechanistically, TRF enhances metabolic flexibility and restores mitochondrial bioenergetic capacity in cerebromicrovascular endothelial cells. Ketone bodies elevated by TRF recapitulate key mitochondrial and vascular effects, improving endothelial respiration, membrane potential, and redox balance in aged mice and primary human brain endothelial cells, but do not fully reproduce neurovascular unit protection. These findings identify endothelial mitochondrial reprogramming as a central mechanism linking dietary timing to cerebrovascular resilience and cognitive preservation, and suggest that metabolic interventions can partially reverse key features of vascular brain aging.

DOI: https://doi.org/10.21203/rs.3.rs-9520035/v1
Schizophrenia (Heidelb). 2026 Jun 08.

A new mechanism underlying mitochondrial dysfunction in schizophrenia - attenuated mRNA transport of the complex I subunit NDUFV2 by its pseudogene NDUFV2P1.

Rachel Karry, Dorit Ben-Shachar.

While schizophrenia (SZ) etiology remains unclear, accumulating evidence implicates mitochondrial dysfunction, particularly complex-I of the respiratory chain and its essential free-electron scavenger subunit, NDUFV2, as a contributor to neuronal and behavioral impairments observed in SZ. Our recent studies suggest a potential role for the NDUFV2 pseudogene (NDUFV2P1) in NDUFV2 deficits. Here, we describe a mechanism by which NDUFV2P1 negatively controls NDUFV2 mRNA transport and its protein levels in SZ-derived lymphocyte cell lines (SZ-LCLs). We found increased NDUFV2P1 transcript levels in SZ frontal cortex postmortem specimens (SZ-FCX) and across all studied SZ-LCLs subcellular fractions. However, NDUFV2 levels were reduced in SZ-FCX and in all cell compartments, except for the nucleus, as compared to healthy subjects-derived LCLs (CTL-LCLs), suggesting its impaired nuclear export. Concomitantly, we observed increased NDUFV2P1, yet decreased NDUFV2 mRNA binding to NXF1, a key player in nuclear mRNA export. Overexpression of NDUFV2P1 in CTL-LCLs mimicked the SZ-state, reducing NDUFV2 levels and its binding to NXF1. The interactome of both mRNAs revealed an opposite binding profile for most RNA-binding proteins (RBPs) in SZ-LCLs compared to CTL-LCLs. Pathway enrichment analysis of the differentially bound RBPs to both transcripts revealed additional potential interference sites for NDUFV2 and NDUFV2P1, including ribosomal-, spliceosome-, and RNA transport-related RBPs. This study uncovers a new mechanism in which NDUFV2P1 interferes with RBPs involved in regulating NDUFV2 transport from the nucleus to mitochondrial-bound ribosomes. While further validation is necessary to substantiate this mechanism, the findings highlight NDUFV2P1 potential as a means for regulating mitochondrial function and consequently energy metabolism in SZ.

DOI: https://doi.org/10.1038/s41537-026-00772-9
J Am Chem Soc. 2026 Jun 09.

Tracking Gene Expression of Single Mitochondria in Live Neurons Using Nanotweezers.

Annie Sahota, Binoy Paulose Nadappuram, Siân C Allerton, Flavie Lesept, Jack H Howden, Suzanne Claxton, Yaxian Liu, Francesco A Aprile, Josef T Kittler, Michael J Devine, Aleksandar P Ivanov, Joshua B Edel.

Neurons are highly polarized cells that depend on mitochondria for energy and signaling homeostasis. Importantly, energy and signaling requirements vary considerably across individual neurons both spatially and temporally. Therefore, to fully understand neuronal mitochondria, methods are needed to analyze mitochondria in live cells over time. The nanotweezer, a minimally invasive single-cell sampling technique, enables precise extraction of individual mitochondria from defined subcellular locations. Here, we combine single-mitochondrial extraction from live neurons with targeted mitochondrial gene expression tracking and mtDNA profiling to develop a platform for live-cell single-mitochondrion tracking and analysis. By tracking the expression of specific mitochondrially encoded genes in the same neurons over time, we reveal preliminary data showing a downregulation of mitochondrial genes MT-ND1 and MT-ATP6 following exposure to α-synuclein aggregates, independent of the proximity of the aggregates to the sampled mitochondria. Our approach provides a proof-of-concept for precise, temporal measurements of mitochondrial composition and targeted gene expression in vitro at single-organelle resolution, opening opportunities for single-cell and single-organelle studies of neuronal mitochondrial heterogeneity and its perturbation in models of neurodegeneration.

DOI: https://doi.org/10.1021/jacs.6c02802