bims-medebr 2026-08-16 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–08–16
23 papers selected by
Regina F. Fernández, Johns Hopkins University

Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.
Energetic crisis, mitochondrial vulnerability and disruption of lactate shuttle in Alzheimer's disease.
Brain energy metabolism changes and neuropsychological impairment in Parkinson disease vs Alzheimer disease.
Metabolic therapeutic targets in Alzheimer's disease.
Altered hippocampal lipid profile underlies anxiety-like behavior secondary to mild traumatic brain injury.
Altered myelin sphingolipid and glycerophospholipid profiles in Huntington disease.
When lactate speaks: Rewiring astrocyte-neuron metabolism in Alzheimer's disease.
Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.
Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.
Cholesterol Drives IFITM3+ Microglia Activation and Induces STING Mediated Neuroinflammation After Ischemic Stroke.
From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.
Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.
Cholesterol restores cortico-striatal synaptic connectivity in Huntington's disease through BDNF-TrkB signalling, supporting a role for cholesterol pathways implicated by human genetic modifier studies.
Brain pro-resolving-to-pro-inflammatory lipids and cPLA2 activation associations with late-life cognitive trajectories.
Emerging roles of CREST superfamily members in lipid metabolism.
Rethinking neurovascular coupling in white matter.
HCAR1-mediated lactate signaling modulates motor behavior and regulates spontaneous firing in Purkinje cells.
Aerobic exercise improves cognition in sepsis-associated encephalopathy by enhancing glucose metabolism through astrocytic GLUT1.
Exploring Pericontusional Temporal Metabolomic Changes after Controlled Cortical Impact in Mice.
Microglial immunometabolism in Alzheimer's disease: A stage-resolved trajectory from adaptive remodeling to the metabolic paradox.
SP1 Aggravates Neonatal Hypoxic-Ischemic Brain Damage by Promoting Ferroptosis Through Transcriptional Upregulation of ACSL4.
Bypassing the bottleneck: Gamma-glutamylcysteine supplementation for brain glutathione enrichment in Alzheimer's disease.
SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.

Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00024-3. [Epub ahead of print]188 363-396

Brain lipid dysregulation as a driver of energy metabolism failure in Alzheimer's disease.

Nitin Yadav, Jyotirmoy Banerjee, Manisha Tiwari, Aparna Dixit.

  Alzheimer's Disease (AD) is becoming more widely recognized as a condition of brain energy metabolism, wherein lipid dysregulation plays a crucial, although unrecognized, role. In addition to functioning as structural elements of neuronal membranes, lipids such as phospholipids, sphingolipids, and cholesterol play a crucial role in regulating mitochondrial bioenergetics, synaptic activity, and membrane-associated signaling pathways. In AD, modifications in lipid composition, distribution, and turnover compromise membrane fluidity, disturb mitochondrial dynamics, and obstruct lipid-mediated transport of energy substrates. These alterations intensify oxidative stress, impair glucose and ketone utilization, and stimulate neuroinflammatory pathways that further diminish metabolic capacity. Progress in lipidomics has uncovered disease-specific lipid signatures, providing a fresh understanding of the relationship between lipid homeostasis and neuronal energy loss. Despite extensive focus on amyloid and tau, lipid-mediated bioenergetic failure remains underrepresented in integrative AD models; this chapter addresses this gap and consolidates existing information connecting lipid modifications to metabolic dysfunction in AD, emphasizing molecular pathways and prospective treatment strategies aimed at lipid metabolism to re-establish bioenergetic equilibrium.

Keywords:  AD; Lipid dysregulation; Lipidomics; Mitochondrial bioenergetics; Neuroinflammation; Therapeutic strategies

DOI:  https://doi.org/10.1016/bs.irn.2026.02.004
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00040-1. [Epub ahead of print]188 67-89

Energetic crisis, mitochondrial vulnerability and disruption of lactate shuttle in Alzheimer's disease.

Gowsika Baskar, Mahesh Kandasamy.

  Alzheimer's disease (AD) has traditionally been characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Emerging evidence reveals that metabolic dysfunction represents a key pathological feature central to disease progression. Mitochondrial dysfunction in AD leads to impaired electron transport chain activity and reduced level of adenosine triphosphate (ATP) synthesis, preceding neurodegeneration and structural abnormalities in cognitive centres of the brain. Early glucose hypometabolism and lactate deprivation or interference with their utilization represent a primary bioenergetic failure driving mitochondrial dysfunction and neuroinflammation prior to the clinical manifestation of AD. While the brain relies on lactate as a prominent energy substrate, astrocytic metabolic defects lead to impaired neuronal energy homeostasis, thereby promoting neurodegeneration. In turn, this metabolic uncoupling could also be associated with defects in regenerative mechanisms by impairing adult neurogenesis in the hippocampus due to energy deprivation, accounting for memory deficits. This chapter discusses the evidence for the energetic crisis in AD, focusing on the disruption of the astrocyte-neuron lactate shuttle (ANLS), hypometabolism of glucose, and mitochondrial vulnerability, as interconnected pathogenic mechanisms. We emphasise cerebral bioenergetic metabolic failure as a central driver of cognitive decline, arising from irreversible reactive gliosis and neuroblastosis mechanisms and highlight various therapeutic options, including restoration of ANLS to mitigate the pathogenesis and memory loss in AD.

Keywords:  Alzheimer's disease; Bioenergetic crisis; Lactate shuttle; Mitochondrial defects; Neurogenesis; Neuroinflammation

DOI:  https://doi.org/10.1016/bs.irn.2026.05.012
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00053-X. [Epub ahead of print]188 33-66

Brain energy metabolism changes and neuropsychological impairment in Parkinson disease vs Alzheimer disease.

Sanaz Khodadadi, Nasim Rezaeimanesh, Ali Ariyae Motahar, Fateme Yousefi, Masoume Avateffazeli, Reyhaneh Montazeri-Shatouri, Elham Hosseini, Sajad Sahab Negah, Abdorreza Naser Moghadasi.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, posing a significant public health risk. Although they are separate diseases, they have similar neuropsychological characteristics. Despite making up only a small portion of total body mass, the brain requires a disproportionately large amount of energy to maintain neuronal activity, synapse function, and cellular homeostasis. Disruption of energy metabolism is thus a major contributor to neurodegeneration. Energy metabolism has a wide-ranging impact on brain function, including cognitive and psychological processes, and gets increasingly compromised in neurodegenerative disorders. This chapter aims to offer a thorough overview of the link between altered brain energy metabolism and neuropsychological impairment in AD and PD.

Keywords:  Alzheimer’s disease (AD); Brain energy metabolism; Cognitive impairment; Glucose hypometabolism; Insulin resistance; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Oxidative stress; Parkinson’s disease (PD)

DOI:  https://doi.org/10.1016/bs.irn.2026.06.001
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00038-3. [Epub ahead of print]188 1-32

Metabolic therapeutic targets in Alzheimer's disease.

Ignatius Raymond Peter L, Debojyoti Chatterjee, A Froilanmark Chrishone, Dileep Francis.

  Alzheimer's disease (AD) is increasingly recognized as a disorder marked not only by amyloid-β and tau pathology, but also by profound disturbances in brain energy metabolism that arise early in disease progression. Accumulating evidence indicates that impairments in glucose utilization, insulin signaling, and mitochondrial function precede neurodegeneration and contribute directly to synaptic failure and cognitive decline. This chapter presents a comprehensive overview of Alzheimer's disease through the lens of metabolic dysfunction, highlighting disrupted neuronal bioenergetics as a central and unifying feature of pathogenesis. We examine key metabolic pathways implicated in AD, including cerebral glucose hypometabolism, brain insulin resistance, impaired glycolysis, mitochondrial oxidative phosphorylation deficits, oxidative stress, and altered mitochondrial dynamics. The chapter further discusses therapeutic strategies aimed at restoring metabolic homeostasis, such as insulin sensitization, enhancement of glucose transport, activation of mitochondrial biogenesis, modulation of the electron transport chain, and the use of mitochondria-targeted antioxidants. In parallel, alternative energy approaches-including ketone metabolism, fatty acid oxidation, and pentose phosphate pathway activation-are explored as promising avenues to bypass glucose-dependent energy deficits and reinforce neuronal resilience. Emerging directions in metabolic therapeutics are also highlighted, including combination treatment strategies, NAD+-sirtuin and AMPK signaling, and the expanding role of the gut microbiome-brain metabolism axis. By integrating insights from experimental models, neuroimaging studies, and clinical trials, this chapter underscores the potential of metabolic interventions to enable early, disease-modifying strategies for Alzheimer's disease.

Keywords:  Alzheimer’s disease; Glucose hypometabolism; Metabolic hypothesis; Metabolic targets; Mitochondria targeted therapy; Neurodegeneration

DOI:  https://doi.org/10.1016/bs.irn.2026.05.010
Mol Cell Biochem. 2026 Aug 08.

Altered hippocampal lipid profile underlies anxiety-like behavior secondary to mild traumatic brain injury.

Celyne Moreira Olimpo, Caroline Amaral Machado, Isadora Helena Pimenta Veloso, Pedro Nepomuceno Parodi, Ana Carolina Feijó Cerqueira Kiryu, Ricardo Tadeu de Carvalho, Antônio L Teixeira, Aline Silva de Miranda, George E G Kluck.

  Traumatic brain injury (TBI) remains a major cause of neurological morbidity worldwide, and mild TBI (mTBI) is frequently associated with emotional disturbances, including anxiety-like behavior. Although classical mechanisms of secondary injury have been extensively characterized, metabolic alterations, particularly those involving cerebral lipid homeostasis, remain incompletely defined. Given the structural and regulatory roles of lipids in the central nervous system, disruption of lipid metabolism may contribute to early post-traumatic dysfunction. We hypothesized that mTBI induces region-specific alterations in brain lipid metabolism and that these changes are associated with anxiety-like behavior during the acute post-injury phase. Adult male C57BL/6 mice were subjected to a weight-drop model of mTBI and evaluated 48-72 h post-injury using different behavioral paradigms. Lipid classes were quantified in the hippocampus, prefrontal cortex, and serum by thin-layer chromatography. mTBI induced anxiety-like behavior without locomotor impairment. Biochemical analyses revealed region-dependent lipid alteration predominantly in the ipsilateral hippocampus, characterized by reduced diacylglycerol and monoacylglycerol levels alongside increased total phospholipids and specific subclasses. Correlation analyses demonstrated significant associations between anxiety-related behavioral parameters and lipid classes across tissues. These findings indicate that mild TBI is accompanied by early, region-specific lipid alterations that are associated with behavioral changes during the acute post-injury period.

Keywords:  Anxiety; Lipids; Metabolism; Trauma brain injury

DOI:  https://doi.org/10.1007/s11010-026-05677-w
J Huntingtons Dis. 2026 Aug 04. 18796397261472539

Altered myelin sphingolipid and glycerophospholipid profiles in Huntington disease.

Michael G Friedrich, Gabrielle R Phillips, Reuben Se Young, Sarah Cameron, Luke K Bale, Jesse A Michael, Huaqi Su, Helena Targa Dias Anastacio, Catriona A McLean, Gavin E Reid, Todd W Mitchell.

  Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT). While classically considered a disease of grey matter, recent imaging data have revealed presymptomatic abnormalities in white matter (WM) tracts. Here, we report lipid changes in glycerophospholipids and sphingolipids from enriched myelin extracts of three WM tracts (internal capsule (IC), dorsomedial prefrontal cortex (dmPFC), corpus callosum (CC)) of HD and control donors. We found no difference in total lipid concentration between HD and control myelin. However, changes were observed at the lipid class level for the CC and dmPFC, with a reduction in the proportion of Hexosylceramides in HD myelin. When lipids were examined at a species level, there was a shift towards shorter glycerophospholipid fatty acid chain length in HD for all three regions, most notably in phosphatidylethanolamine species. This coincides with previous data showing a reduction in fatty acyl chain lengths in sphingolipid species in the caudate of the same donor cohort and suggests a widespread impact of HD on fatty acid metabolism in the brain.

Keywords:  Huntington's disease; glycerophospholipids; myelin; sphingolipid; white matter

DOI:  https://doi.org/10.1177/18796397261472539
Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00192-0. [Epub ahead of print]38(8): 1527-1528

When lactate speaks: Rewiring astrocyte-neuron metabolism in Alzheimer's disease.

Jessica Furtado, Marc Schneeberger.

Metabolic dysfunction is a defining but poorly understood feature of Alzheimer's disease. Du et al. show that a brain-penetrant GLP-1 receptor agonist rewires astrocyte-neuron metabolic coupling through lactate-driven histone lactylation, linking astrocytic glycolysis to neuronal lipid homeostasis and positioning metabolite signaling as a therapeutic axis in neurodegeneration.

DOI: https://doi.org/10.1016/j.cmet.2026.05.007
Cells. 2026 Aug 03. pii: 1404. [Epub ahead of print]15(15):

Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.

Md Riad Chowdhury, Gui-Hwa Jeong, In-Kyu Lee.

  Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD+ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS-STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan.

Keywords:  NLRP3; PDK4; SASP; aging; inflammaging; meta-inflammation; mitochondrial dysfunction; mitophagy; mtROS; pyruvate dehydrogenase

DOI:  https://doi.org/10.3390/cells15151404
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00045-0. [Epub ahead of print]188 231-271

Brain energy crisis in Alzheimer's and Parkinson's disease: Nanotechnology as a therapeutic strategy.

Mohini Milmile, Shweta Singh, Ajay Pandey, Gajanan Pawar, Pradnya Petkar, Yogesh Chander, Ranjan Mishra, Ruchi Chawla.

  Alzheimer's disease and Parkinson's disease are increasingly recognized as disorders marked not only by protein aggregation but by a sustained failure of brain energy metabolism. Years before overt cognitive or motor symptoms emerge, neurons begin to experience impaired glucose utilization, mitochondrial dysfunction, and declining ATP production. Because the brain is highly energy-dependent, even subtle metabolic disturbances can disrupt synaptic function, impair neuronal signaling, and trigger oxidative stress. As mitochondrial efficiency declines, reactive oxygen species accumulate, inflammatory pathways become chronically activated, and damaged cellular components are insufficiently cleared, creating a vicious cycle that accelerates neurodegeneration. Conventional metabolic therapies, including antioxidants and mitochondrial cofactors, have produced limited clinical success, largely due to poor penetration across the blood-brain barrier and lack of specificity for vulnerable neuronal populations and intracellular targets such as mitochondria. Nanotechnology introduces a more precise therapeutic strategy by enabling targeted delivery of metabolic modulators directly to the brain. Engineered nanocarriers can be designed to cross biological barriers, enhance drug stability, and release therapeutic agents in a controlled or stimuli-responsive manner within diseased regions. Advanced systems including polymeric nanoparticles, lipid-based carriers, intranasal nano formulations, biomimetic vesicles, and catalytic nanozymes offer the ability to simultaneously modulate oxidative stress, restore mitochondrial function, and regulate neuroinflammation. By integrating delivery precision with metabolic intervention, neuro-nanomedicine shifts the therapeutic focus from symptomatic management toward addressing the underlying bioenergetic crisis. Although challenges remain in safety validation, scalability, and clinical translation, targeted nanotherapeutic strategies hold significant promise for transforming the treatment landscape of these debilitating neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Bioenergetics; Nanotechnology; Parkinson’s disease

DOI:  https://doi.org/10.1016/bs.irn.2026.05.016
CNS Neurosci Ther. 2026 Aug;32(8): e71073

Cholesterol Drives IFITM3+ Microglia Activation and Induces STING Mediated Neuroinflammation After Ischemic Stroke.

Yue Cheng, Yuxi Zhou, Yonghui Chen, Tianni Shen, Yan Li, Chen Chen, Qiuyue Fan, Jie Qi, Peiying Li, Yueman Zhang.

   AIMS: Cerebral ischemic stroke triggers extensive neuronal membrane breakdown, releasing a massive load of cholesterol that overwhelms resident microglia. Dysregulated microglial cholesterol metabolism has been implicated in post-stroke neuroinflammation, yet the specific pathogenic microglial subpopulations, their molecular signatures, and the downstream inflammatory cascades remain poorly defined.
METHODS: We employed a permanent distal middle cerebral artery occlusion (dMCAO) model combined with single-cell RNA sequencing (scRNA-seq) to profile immune cell transcriptomes and identify cholesterol-associated microglial markers. Cholesterol dynamics, lipid droplet accumulation, and inflammatory marker expression were quantified via immunofluorescence and transmission electron microscopy. Therapeutic interventions included pharmacological cholesterol mobilization with 2-hydroxypropyl-β-cyclodextrin (HβCD), pharmacological STING inhibition with C-176, and microglia-targeted STING knockdown using AAV9 vectors. Cerebral injury and neurological function were assessed through infarct volume measurement, white matter integrity analysis, and behavioral assays (rotarod and grip strength) in dMCAO, tMCAO, and perioperative stroke (PIS) models.
RESULTS: Using scRNA-seq, we identified interferon-induced transmembrane protein 3 (IFITM3) as a specific marker for a microglial subpopulation that was characterized by upregulated ACAT1, enhanced cholesterol esterification, and accumulation of cholesterol crystals and lipid droplets. This IFITM3+ microglia population peaked at 7 days post-stroke and correlated with NLRP3 inflammasome activation and STING signaling. Pharmacological reduction of cholesterol burden with HβCD attenuated lipid droplet formation, suppressed mitochondrial DNA leakage, and inhibited STING pathway activation. Correspondingly, HβCD and C-176 administration significantly reduced cerebral infarct size, mitigated white matter demyelination, and improved motor function in dMCAO and tMCAO models. We further found that AAV-mediated STING knockdown recapitulated the above protective effects in HβCD and C-176 treated stroke mice. Furthermore, HβCD treatment ameliorated microglial inflammation and improved functional outcomes in a PIS model.
CONCLUSION: IFITM3+ microglia is a pro-inflammatory and cholesterol-laden subpopulation that exacerbates post-stroke cerebral ischemic brain injury. Targeting the microglial cholesterol axis by HβCD or inhibiting the STING pathway represents a promising therapeutic strategy to mitigate ischemic brain injury and improve neurological function.

Keywords:  STING; cholesterol; ischemic stroke; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/cns.71073
J Inherit Metab Dis. 2026 Sep;49(5): e70239

From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.

Ivano Di Meo, Yair Anikster, Valeria Tiranti, Arcangela Iuso.

  Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in PANK2, PPCS, PPCDC, and COASY cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: PANK2 and COASY defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas PPCS and PPCDC deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, COASY variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in PPCS and PPCDC deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4'-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.

Keywords:  COASY; PANK2; PPCDC; PPCS; coenzyme A (CoA); neurodegeneration with brain iron accumulation (NBIA)

DOI:  https://doi.org/10.1002/jimd.70239
Aging Cell. 2026 Aug;25(8): e70660

Metabolic Reprogramming of Brain Microglia: Implications for Aging and Aging-Associated Neurodegenerative Diseases.

Seokjo Kang, Helen S Goodridge.

  Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity. In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression. Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.

Keywords:  Alzheimer's disease; Parkinson's disease; brain aging; metabolism; microglia; neuroinflammation; sex differences

DOI:  https://doi.org/10.1111/acel.70660
Pharmacol Res. 2026 Aug 12. pii: S1043-6618(26)00290-2. [Epub ahead of print] 108375

Cholesterol restores cortico-striatal synaptic connectivity in Huntington's disease through BDNF-TrkB signalling, supporting a role for cholesterol pathways implicated by human genetic modifier studies.

Allegra Lenci, Michela Villa, Andrea Scolz, Giulia Birolini, Paola Conforti, Giuseppe Pepe, Antonio Nicolas Castagno, Christian Cassarino, Laura Colombo, Monica Favagrossa, Antonino Polimeno, Linda Ottoboni, Stefania Corti, Alba Di Pardo, Mario Salmona, Vittorio Maglione, Chiara Zuccato, Elena Cattaneo.

  Cortico-striatal synaptic dysfunction is an early hallmark of Huntington's disease (HD), yet the mechanisms underlying synapse loss and its reversibility remain poorly understood. Brain cholesterol is essential for neuronal and synaptic function, and dysregulated cholesterol metabolism has emerged as a key feature of HD, with reduced cholesterol biosynthesis reported in rodent models and cholesterol replenishment shown to be beneficial. Consistent with these findings, GWAS identified HD modifier loci outside canonical DNA repair pathways, including MED15, which among its functions supports SREBF2-mediated transcription of cholesterol biosynthesis genes, and a chr22 locus encompassing SREBF2, the master regulator of cholesterol biosynthesis. These findings suggest that pathways regulating cholesterol homeostasis may contribute to modifying the course of HD. Here, we show that increasing cholesterol availability prevents synapse loss and restores cortico-striatal connectivity in HD models. Cholesterol supplementation restores excitatory synapse density in vivo and in vitro. In primary HD neurons, cholesterol stabilizes dendritic spines and promotes the enrichment of GluA1-containing AMPA receptors in mature mushroom spines during chemically induced long-term potentiation, consistent with improved synaptic plasticity. Using microfluidic devices to spatially resolve the cortico-striatal circuit, we identified a compartment-specific mechanism whereby cholesterol delivery to cortical neurons is necessary and sufficient to restore cortico-striatal connectivity, whereas cholesterol administration to the striatal compartment selectively restores intra-striatal inhibitory synapses. Mechanistically, NMDA receptor and BDNF/TrkB signalling mediate the cholesterol-dependent restoration of synaptic connectivity, establishing cholesterol as a critical regulator of cortico-striatal synaptic integrity in HD and supporting targeting cholesterol homeostasis as a therapeutic strategy to restore synaptic function.

Keywords:  BDNF; Huntington’s disease; TrkB; cholesterol; cortico-striatal synapse; synaptic dysfunction

DOI:  https://doi.org/10.1016/j.phrs.2026.108375
EBioMedicine. 2026 Aug 12. pii: S2352-3964(26)00305-1. [Epub ahead of print]131 106421

Brain pro-resolving-to-pro-inflammatory lipids and cPLA2 activation associations with late-life cognitive trajectories.

Anat Yaskolka Meir, Xinhui Wang, Boyang Li, Robert S Wilson, David A Bennett, Stan G Louie, Hussein N Yassine, Zoe Arvanitakis.

   BACKGROUND: Lipidome alterations are linked to neurodegenerative disorders, but the association between calcium-dependent phospholipase A2 (cPLA2)-related lipid ratios, which reflect pro-resolving and pro-inflammatory lipid biology, and age-related cognitive decline remains unclear.
METHODS: In postmortem dorsolateral prefrontal cortex samples from participants in the Religious Orders Study and the Rush Memory and Aging Project (lipidomics n = 191; transcriptomics n = 411), we quantified three ratios of cPLA2-released fatty acid precursors (primary exposures), three indices of arachidonic acid (AA) metabolism, and two AA transcriptomic activation scores (secondary exposures). Global cognition (primary outcome) and five cognitive domains were derived from annual neuropsychological testing.
FINDINGS: In mixed-effect change point models (death-age, sex, education, and apolipoprotein E ε4 (APOEε4)-adjusted), higher brain eicosapentaenoic acid/AA was associated with better global cognition proximate-to-death (β = 0.254, 95% CI [0.064-0.455]) and a slower rate of cognitive decline (β = 0.045, 95%CI [0.005-0.081]). Separate models including an APOEε4 × cPLA2 lipid-ratio interaction showed that the association between lipoxin A4/AA and global cognition proximate-to-death differed significantly between APOEε4 carriers and non-carriers (β = 0.396, 95% CI [0.015-0.776]). A secondary analysis, repeating these models with three indices of AA metabolism-to-AA ratios and examining the association between the six cPLA2 lipid ratios and five cognition domains, yielded similar results. Higher AA transcriptomic activation scores, indicating greater cPLA2 activation, were associated with lower global cognition at death (β = -0.148, 95% CI [-0.266 to -0.028]) and with multiple cognitive domains.
INTERPRETATION: Modulation of brain lipid ratios warrants further investigation as a potential target related to cognitive decline.
FUNDING: National Institute of Health, the Council for Higher Education-Zuckerman support program for outstanding postdoctoral female researchers.

Keywords:  Arachidonic acid; Brain autopsy; Docosahexaenoic acid; Eicosapentaenoic acid; Lipidomics; Phospholipase A2; Postmortem neuropathology; Transcriptomics

DOI:  https://doi.org/10.1016/j.ebiom.2026.106421
J Lipid Res. 2026 Aug 04. pii: S0022-2275(26)00147-1. [Epub ahead of print] 101117

Emerging roles of CREST superfamily members in lipid metabolism.

Takuma Takagaki, Tomoyoshi Shingaki, Nozomu Kono, Junken Aoki.

  CREST superfamily members are a series of multi-transmembrane proteins conserved across a wide range of species. There are approximately 20 members in mammals. CREST superfamily members have been assigned various functions, including those of receptors, transporters, enzymes, and membrane fusion factors. Recent functional and structural analyses of CREST superfamily members have revealed that all members possess a structure resembling an enzymatic active site that catalyzes hydrolysis reactions. Furthermore, it is becoming increasingly clear that they interact with various membrane lipids and are involved in lipid metabolism. This review summarizes current knowledge of the structure and function of each CREST superfamily member and explores their potential as lipid-metabolizing enzymes.

Keywords:  CREST; GPI; PAQR; adiponectin receptor; ceramidase; ceramide; phospholipase; phospholipid

DOI:  https://doi.org/10.1016/j.jlr.2026.101117
Trends Endocrinol Metab. 2026 Aug 13. pii: S1043-2760(26)00197-9. [Epub ahead of print]

Rethinking neurovascular coupling in white matter.

Carlos Matute.

  Neurovascular coupling (NVC) is associated with activity-dependent functional hyperemia in gray matter. White matter may operate under distinct vascular-metabolic principles. We propose that white matter operates through a reserve-based form of NVC in which local energetic reserves help sustain energy homeostasis despite transient mismatches between metabolic demand and vascular supply.

Keywords:  brain energetics; energy homeostasis; glial metabolism; metabolic buffering; neurovascular coupling; white matter

DOI:  https://doi.org/10.1016/j.tem.2026.07.011
iScience. 2026 Aug 21. 29(8): 116930

HCAR1-mediated lactate signaling modulates motor behavior and regulates spontaneous firing in Purkinje cells.

Francesca Binda, Lara Buscemi, Nicolas Gurtner, Lorenz Hirt, Jean-Yves Chatton.

  Lactate modulates several phenomena ranging from gene transcription to plasticity. Through its specific GPCR receptor HCAR1, lactate acts as a signaling molecule modulating neuronal excitability. Silencing lactate signaling promotes anxiety-like behavior and worsens epileptic seizures, highlighting the central role of HCAR1 in brain function. HCAR1 expression in the cerebellum supports the role of the receptor in motor coordination. Early experimental evidence suggesting HCAR1 expression in cerebellar Purkinje cells (PCs) together with its ability to modulate neuronal excitability qualifies the receptor as a possible modulator of PC activity with important implications for cerebellar-mediated diseases. This hypothesis was investigated using behavioral analysis and ex vivo electrophysiology that showed gait instability and motor learning defects in HCAR1 knockout mice associated with increased PC firing. We identified HCN channels as the downstream target of HCAR1. We conclude that lactate signaling is a modulator of PC excitability and revealed the HCAR1 role in motor behavior.

Keywords:  HCAR1; HCN; Purkinje cells; cerebellum; glia; hydroxycarboxylic acid receptor 1; lactate; motor learning; spontaneous firing

DOI:  https://doi.org/10.1016/j.isci.2026.116930
Exp Neurol. 2026 Aug 08. pii: S0014-4886(26)00321-3. [Epub ahead of print] 115956

Aerobic exercise improves cognition in sepsis-associated encephalopathy by enhancing glucose metabolism through astrocytic GLUT1.

Wenbo Liu, Qiuting Zeng, Wenlan Cai, Fangming Shen, Yuzhou Chen, Hongyu Dai, Daoyun Lei, Jiaojiao Yang, Shuya Jin, Yisi Lu, Xiangyang Zhang, Hui Zhang, Jie Sun.

  Sepsis-associated encephalopathy (SAE) is a common neurological complication of sepsis and a major cause of persistent cognitive impairment in survivors. In recent years, aerobic exercise has attracted increasing attention for its potential roles in improving neural function, regulating systemic metabolism, and preserving cognitive performance; however, whether prior aerobic exercise can mitigate acute sepsis-induced cognitive impairment and its underlying mechanisms remains to be elucidated. Two-sample Mendelian randomization analysis showed that genetically predicted physical activity was associated with a reduced risk of 28-day sepsis mortality. Animal experiments further demonstrated that four weeks of aerobic exercise preconditioning significantly improved cognitive performance in LPS-induced SAE mice, as evidenced by increased spontaneous alternation in the Y-maze and prolonged freezing time in the conditioned fear test. Mechanistically, at day 7 after LPS administration, SAE mice exhibited decreased hippocampal glucose uptake, abnormal glycogen accumulation in the dentate gyrus (DG), and reduced lactate dehydrogenase activity, accompanied by downregulation of astrocytic glucose transporter 1 (GLUT1), decreased expression of synaptic proteins Postsynaptic Density Protein 95 (PSD95) and Synapsin I, and impaired dendritic structure. Aerobic exercise maintained astrocytic GLUT1 expression in the DG and restored hippocampal glucose uptake, thereby alleviating cerebral glucose metabolic disturbances and mitigating synaptic injury. In vitro, LPS stimulation downregulated GLUT1 expression in primary astrocytes and, in an astrocyte-neuron co-culture system, led to reduced neuronal synaptic protein expression through impaired astrocytic support. In vivo overexpression of astrocytic GLUT1 partially recapitulated the protective effects of aerobic exercise on glucose metabolism, synaptic structure, and cognitive function. Collectively, these findings suggest that aerobic exercise attenuates SAE-related cognitive impairment by counteracting the downregulation of astrocytic GLUT1 in the hippocampal DG, thereby maintaining glucose transport, preserving metabolic homeostasis, and protecting synaptic plasticity. These results further support regular aerobic exercise in daily life as a potential non-pharmacological strategy and provide new insights for the prevention and intervention of SAE.

Keywords:  Aerobic exercise; Astrocytes; Cognitive impairment; Dentate gyrus; GLUT1; Glucose metabolism; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.expneurol.2026.115956
J Neurotrauma. 2026 Aug 11. 8977151261475262

Exploring Pericontusional Temporal Metabolomic Changes after Controlled Cortical Impact in Mice.

Amanda M Dave, Helena C Oft, Sambodh Sinha, Keri Janesko-Feldman, Vincent Vagni, Steven Mullett, Stacy Gelhaus, Patrick Kochanek, Robert S B Clark, Hulya Bayir, Dennis W Simon.

  Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality, yet metabolic responses in the injured brain remain incompletely understood. Metabolomic profiling of pericontusional tissue may enable the identification of acute-phase biomarkers and reveal novel therapeutic targets. Using a controlled cortical impact (CCI) model, we performed targeted metabolomic analysis of tricarboxylic acid (TCA) cycle intermediates, amino acids, and acylcarnitines at multiple time points within the first 72 h postinjury. We hypothesize that there is time-dependent mitochondrial dysfunction and impaired β-oxidation in the acute and sub-acute time points after injury. CCI was performed in adult male C57BL6/J mice (velocity 5 m/s, depth 1.2 mm) under isoflurane anesthesia. Pericontusional tissue was harvested at 2, 6, 24, and 72 h postinjury following transcardial saline perfusion (n = 8/group). Naïve and anesthesia-only sham animals served as controls; sham animals received isoflurane exposure without craniotomy to isolate anesthetic effects from surgical injury. Relative quantification of TCA cycle intermediates, amino acids, and acylcarnitines was performed by liquid chromatography-high resolution mass spectrometry; metabolite abundances were normalized to protein content. Data were analyzed by Student's t-test, and p value < 0.05 determined significance. Enrichment analysis of metabolite profiles was conducted and visualized in MetaboAnalyst 6.0. Pericontusional tissue demonstrated time-dependent changes across the three metabolite classes, with two distinct temporal phases identified by dimensionality reduction: an acute phase (2-6 h) and a subacute phase (24-72 h). TCA cycle intermediates and glycolytic metabolites were broadly and progressively depleted, consistent with sustained mitochondrial dysfunction and energy failure. Acylcarnitines accumulated across multiple chain lengths, indicating impaired fatty acid β-oxidation. Amino acid profiles showed broad accumulation of essential and branched-chain amino acids-notably leucine and valine-alongside depletion of glutamate, alanine, and GABA, contrasting with prior reports of branch-chain amino acids depletion after TBI. Ingenuity Pathway Analysis confirmed broad suppression of amino acid catabolism, carbohydrate metabolism, and lipid oxidation pathways after CCI. Tryptophan catabolism via the kynurenine pathway was the sole upregulated metabolic pathway, consistent with indoleamine 2,3-dioxygenase 1-mediated neuroinflammatory signaling. We identified TBI-dependent alterations in key metabolic pathways within pericontusional tissue that may have implications for the development of biomarkers or metabolism-targeted therapies. Future investigations should explore cell type-specific metabolic changes and assess their correlation with clinically measurable metabolite levels.

Keywords:  TCA cycle; acylcarnitine; controlled cortical impact; metabolomics; mitochondria; time-dependent

DOI:  https://doi.org/10.1177/08977151261475262
Biomed Pharmacother. 2026 Aug 08. pii: S0753-3322(26)00877-2. [Epub ahead of print]202 119841

Microglial immunometabolism in Alzheimer's disease: A stage-resolved trajectory from adaptive remodeling to the metabolic paradox.

Yue Zou, Yi Ou, Hang Zhao, Ge Chen, Zhong Chen, Yunqin Li, Junliang Jiang.

  Microglia are central regulators of the cellular phase of Alzheimer's disease (AD). Under chronic exposure to amyloid-β, pathological tau, and aging-associated bioenergetic decline, these cells undergo immunometabolic remodeling that may initially be adaptive. As stress persists, this remodeling can become maladaptive, marked by disordered glycolysis, disturbed lipid handling, mitochondrial dysfunction, and compensatory failure. In this review, we organize these changes as a stage-dependent trajectory from adaptive remodeling to functional decompensation. We introduce the "metabolic paradox" as an operational descriptor: a concurrent, same-cell mismatch between increased substrate uptake or inflammatory activation and declining bioenergetic efficiency and homeostatic function. Along this trajectory we examine neurovascular energy bottlenecks, substrate redistribution, triggering receptor expressed on myeloid cells 2 (TREM2)/apolipoprotein E (APOE)-dependent lipid homeostasis, mitochondrial and proteostatic collapse, and their links to persistent neuroinflammation, defective phagocytosis, aberrant synaptic pruning, and senescence-like dysfunction. We synthesize prior primary findings and stratify each major claim by evidentiary strength, avoiding the overinterpretation of model-specific results as patient-level mechanisms. Finally, we frame immunoprevention as mechanism-based, early-stage metabolic intervention to preserve homeostatic microglial function, a strategy whose clinical benefit remains a hypothesis requiring prospective testing.

Keywords:  Alzheimer’s disease; Glycolysis; Immunometabolism; Lipid metabolism; Microglia

DOI:  https://doi.org/10.1016/j.biopha.2026.119841
ASN Neuro. 2026 ;18(1): 2708346

SP1 Aggravates Neonatal Hypoxic-Ischemic Brain Damage by Promoting Ferroptosis Through Transcriptional Upregulation of ACSL4.

Shuting Chang, Weiqing Huang, Biao Yi, Chenchao Fu.

  Neonatal hypoxic-ischemic brain damage (HIBD) is a major cause of neurological disability. This study investigated the role of the transcription factor specificity protein 1 (SP1) and its target, Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), in regulating ferroptosis in neonatal HIBD. Using a neonatal mouse HIBD model and an in vitro neuronal oxygen-glucose deprivation/reperfusion (OGD/R) model, we applied gene knockdown/overexpression and pharmacological tools, analyzed via molecular and histological techniques. Ferroptosis was activated in HIBD. Hypoxic-ischaemic injury upregulated SP1, which transcriptionally activated ACSL4 by binding its promoter. SP1 knockdown attenuated neuronal and brain injury, reducing lipid peroxidation and iron accumulation while improving cell viability and cognitive function. These protections were abolished by ACSL4 overexpression or erastin co-treatment, and were associated with suppression of the ACSL4-dependent ferroptotic pathway. The SP1/ACSL4 axis critically aggravates neonatal hypoxic-ischaemic brain damage by promoting ferroptosis, representing a promising therapeutic target.

Keywords:  ACSL4; HIBD; SP1; ferroptosis

DOI:  https://doi.org/10.1080/17590914.2026.2708346
J Alzheimers Dis. 2026 Aug 13. 13872877261474009

Bypassing the bottleneck: Gamma-glutamylcysteine supplementation for brain glutathione enrichment in Alzheimer's disease.

Pravat K Mandal, George Perry, Joseph C Maroon, Patricia Corby, Riddhi Patira, Oscar L Lopez.

  Alzheimer's disease (AD) is a major neurodegenerative disorder affecting more than 7 million Americans. Extensive studies have identified various factors associated with the development of AD, but the actual cause remains unknown. Transgenic mouse model and human studies strongly indicate that oxidative stress precedes amyloid-β plaque formation and tau phosphorylation in AD. GSH loss itself raises the Abeta42/Abeta40 ratio and promotes tau aggregation [5], placing GSH depletion upstream of classical AD pathology. Subsequently, the role of the master antioxidant, glutathione (GSH), came into focus for brain GSH level enrichment through supplementation with γ-glutamylcysteine (GGC), the immediate precursor of GSH. We present that GGC has an excellent safety record and bioavailability. GGC is a strong candidate to investigate for brain GSH enrichment (target engagement hippocampus, anterior cingulate cortex etc.) and subsequent cognitive enhancement for patients with mild cognitive impairment (MCI).

Keywords:  GSH conformers; MEGA-PRESS; antioxidant; brain imaging; clinical trial; enrichment; gamma-glutamylcysteine; glutathione; magnetic resonance spectroscopy; mild cognitive impairment

DOI:  https://doi.org/10.1177/13872877261474009
Brain Behav Immun. 2026 Aug 10. pii: S0889-1591(26)00701-4. [Epub ahead of print] 106953

SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.

Xiaoman Dai, Ziling Ye, Xujun Zhang, Yufei Huang, Chen Wang, Yanling Liu, Boya Gao, Jing Zhang, Xiaochun Chen.

  Metabolic dysfunction in microglia is increasingly recognized as a core driver of Alzheimer's disease (AD) pathogenesis, and yet the underlying mechanisms remain elusive. Here, we identified salt-inducible kinase 2 (SIK2) as a critical metabolic checkpoint that was downregulated in microglia across the AD mouse models (5 × FAD, APP/PS1, and SAMP8). We found that a loss of SIK2 in microglia induced a pro‑inflammatory phenotype, thus impairing amyloid β-protein (Aβ) phagocytosis and rewiring glucose and lipid metabolism toward enhanced glycolysis and lipid accumulation. Mechanistically, SIK2 directly interacted with the histone acetyltransferase P300; SIK2 deficiency increased the activity of P300, elevating H3K9 acetylation and H4K8/12 lactylation at promoters of metabolic genes. The microglia‑specific SIK2 overexpression in the 5 × FAD mice mitigated cognitive deficits, Aβ pathology, neuroinflammation, and aberrant histone modifications. A pharmacological inhibition of P300 regained these protective effects. Our findings highlight the SIK2-P300 epigenetic axis as a key regulator of the metabolic homeostasis in microglia and a potential therapeutic target for AD treatments.

Keywords:  Acetylation; Alzheimer’sdisease; Lactylation; Metabolic reprogramming; Neuroinflammation; P300; Salt-inducible kinase 2

DOI:  https://doi.org/10.1016/j.bbi.2026.106953