bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–04–06
nine papers selected by
Regina F. Fernández, Johns Hopkins University
  1. New insight into the role of altered brain cholesterol metabolism in the pathogenesis of AD: A unifying cholesterol hypothesis and new therapeutic approach for AD.
  2. The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
  3. Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.
  4. Strategic delivery of omega-3 fatty acids for modulating inflammatory neurodegenerative diseases.
  5. Mitochondrial and peroxisomal fission in cortical neurogenesis.
  6. Molecular elucidation of brain lipofuscin in aging and Neuronal Ceroid Lipofuscinosis.
  7. Cell membranes sustain phospholipid imbalance via cholesterol asymmetry.
  8. Associations between plasma 24(S)-Hydroxycholesterol and neuropsychological profile in Fragile X Syndrome.
  9. α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
  1. Brain Res Bull. 2025 Mar 29. pii: S0361-9230(25)00133-9. [Epub ahead of print]224 111321
    New insight into the role of altered brain cholesterol metabolism in the pathogenesis of AD: A unifying cholesterol hypothesis and new therapeutic approach for AD.
    Xiaobo Yang, Kai Yao, Mengqi Zhang, Wenbin Zhang, Hengbing Zu.
      The dysregulation of cholesterol metabolism homeostasis has been universally suggested in the aeotiology of Alzheimer's disease (AD). Initially, studies indicate that alteration of serum cholesterol level might contribute to AD. However, because blood-brain barrier impedes entry of plasma cholesterol, brain cells are not directly influenced by plasma cholesterol. Furthermore, mounting evidences suggest a link between alteration of brain cholesterol metabolism and AD. Interestingly, Amyloid-β proteins (Aβ) can markedly inhibit cellular cholesterol biosynthesis and lower cellular cholesterol content in cultured cells. And Aβ overproduction/overload induces a significant decrease of brain cellular cholesterol content in familial AD (FAD) animals. Importantly, mutations or polymorphisms of genes related to brain cholesterol transportation, such as ApoE4, ATP binding cassette (ABC) transporters, low-density lipoprotein receptor (LDLR) family and Niemann-Pick C disease 1 or 2 (NPC1/2), obviously lead to decreased brain cholesterol transport, resulting in brain cellular cholesterol loss, which could be tightly associated with AD pathological impairments. Additionally, accumulating data show that there are reduction of brain cholesterol biosynthesis and/or disorder of brain cholesterol trafficking in a variety of sporadic AD (SAD) animals and patients. Collectively, compelling evidences indicate that FAD and SAD could share one common and overlapping neurochemical mechanism: brain neuronal/cellular cholesterol deficiency. Therefore, accumulated evidences strongly support a novel hypothesis that deficiency of brain cholesterol contributes to the onset and progression of AD. This review highlights the pivotal role of brain cholesterol deficiency in the pathogenesis of AD. The hypothesis offers valuable insights for the future development of AD treatment.
    Keywords:  Alzheimer's disease; Cholesterol; Familial Alzheimer's disease; Pathogenesis; Sporadic Alzheimer's disease; Therapy
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111321
  2. bioRxiv. 2025 Mar 27. pii: 2025.03.19.644244. [Epub ahead of print]
    The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
    Sahan Bs Kansakar, Sydney P Sterben, Charitha C Anamala, Mitchell D Thielen, Volha Liaudanskaya.
      Traumatic brain injury (TBI) is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD), yet the mechanistic link remains unclear. Here, we integrated human patient-derived transcriptomics with a 3D in vitro brain injury model to dissect cell-specific mitochondrial dysfunction as a driver of injury-induced neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a novel cell-specific mitochondria tracking system, we demonstrate prolonged neuronal mitochondrial fragmentation, bioenergetic failure, and metabolic instability, coinciding with the emergence of AD markers, including pTau, APP, and Aβ42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes impaired metabolic support and microglia sustained chronic inflammation. These findings establish neuronal mitochondrial failure as an early trigger of injury-induced neurodegeneration, reinforcing mitochondrial dysfunction as a therapeutic target for preventing TBI-driven AD pathology.
    DOI:  https://doi.org/10.1101/2025.03.19.644244
  3. Neurobiol Aging. 2025 Mar 24. pii: S0197-4580(25)00057-0. [Epub ahead of print]151 1-12
    Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.
    Daniel A Adekunbi, Hillary F Huber, Gloria A Benavides, Ran Tian, Cun Li, Peter W Nathanielsz, Jianhua Zhang, Victor Darley-Usmar, Laura A Cox, Adam B Salmon.
      Mitochondria play a crucial role in brain homeostasis and changes in mitochondrial bioenergetics are linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. We assessed mitochondrial bioenergetics from archived prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when normalized for citrate synthase activity, suggesting that the decline is predominantly driven by changes in the specific activity of individual complexes rather than global changes in mitochondrial content. When donor sex was used as a covariate, we found that ETC activity was preserved with age in females and declined in males. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity at a given age relative to females. Circulating cortisol negatively correlated with walking speed when male and female data were combined. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a link between frailty and PFC bioenergetic function and highlights a potential molecular mechanism for sexual dimorphism in brain resilience.
    Keywords:  Aging; Baboons; Cortisol; Mitochondrial respiration; Prefrontal cortex; Walking speed
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2025.03.010
  4. Front Aging Neurosci. 2025 ;17 1535094
    Strategic delivery of omega-3 fatty acids for modulating inflammatory neurodegenerative diseases.
    Yixin Chen, Roni Touboul, Yao Chen, Chuchun L Chang.
       Objectives: Early-life inflammatory events like infections and injuries may predispose the brain to Alzheimer's disease (AD) by disrupting neurodevelopment and raising vulnerability. The association between early neuroinflammation and subsequent neurodegeneration leading to dementia remains unclear. We hypothesize that omega-3 (n-3) fatty acids (FA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), positively regulate neuro-immune cells, preserving their cell membrane structure and metabolic homeostasis. Our study examined whether strategic delivery of n-3 FA via injectable n-3 triglycerides (TG) can influence microglial lipid metabolism to prevent or delay AD progression.
    Methods and results: We characterized n-3 treatment effects on modulating lipid and metabolic homeostasis in microglia during the critical window of brain development. Our preliminary studies on determining the effects of early n-3 treatment on brain cell homeostasis indicate that perinatal bolus n-3 TG injections suppressed activation of gliosis-associated markers in young mice predisposed to AD (5xFAD) and yielded sustained regulatory effects on the expression of inflammatory molecules, such as interleukin-6 (Il6) and tumor necrosis factor-alpha (Tnfα), in adult brains. A significant increase in high-frequency ultrasonic vocalizations (USV) was observed in P6 5xFAD mice that received perinatal n-3 compared to vehicle control, implicating enhanced active communication patterns. Improvement in behavior deficits was observed in n-3-treated adult AD mice. Perinatal n-3 TG treatment modified brain lipid composition in young offspring, increasing key membrane lipid species, such as phospholipids (PL) and lysophospholipids (lysoPL). Pro-inflammatory sphingolipids associated with neurodegeneration, including lactosylceramide, were significantly lower in mice treated with n-3 than those in saline-treated AD mice.
    Conclusion: Our study establishes a proof of principle for targeting brain immune cell metabolism with injectable n-3 TG to mitigate neuroinflammation in AD pathogenesis, paving the way for future research into early treatments for related central nervous system (CNS) disorders.
    Keywords:  5xFAD; Alzheimer’s disease; fatty acids; microglia; neuroinflammation; omega-3
    DOI:  https://doi.org/10.3389/fnagi.2025.1535094
  5. Int J Biochem Cell Biol. 2025 Mar 28. pii: S1357-2725(25)00041-X. [Epub ahead of print]182-183 106774
    Mitochondrial and peroxisomal fission in cortical neurogenesis.
    Gabriella L Robertson, Caroline Bodnya, Vivian Gama.
      The human brain is unique in its cellular diversity, intricate cytoarchitecture, function, and complex metabolic and bioenergetic demands, for which mitochondria and peroxisomes are essential. Mitochondria are multifunctional organelles that coordinate various signaling pathways central to neurogenesis. The dynamic morphological changes of the mitochondrial network have been linked to the regulation of bioenergetic and metabolic states. Specific protein machinery is dedicated to mitochondrial fission and fusion, allowing organelle distribution during cell division, organelle repair, and adaptation to environmental stimuli (excellent reviews have been published on these topics [Kondadi and Reichert, 2024; Giacomello et al., 2020; Tilokani et al., 2018; Kraus et al., 2021; Navaratnarajah et al., 2021]). In parallel, peroxisomes contain over 50 different enzymes which regulate metabolic functions that are critical for neurogenesis (Berger et al., 2016; Hulshagen et al., 2008). Peroxisomes share many of the components of their fission machinery with the mitochondria and undergo fission to help meet metabolic demands in response to environmental stimuli (Schrader et al., 2016). This review focuses primarily on the machinery involved in mitochondrial and peroxisomal fission. Mitochondrial fission has been identified as a critical determinant of cell fate decisions (Iwata et al., 2023, 2020; Khacho et al., 2016; King et al., 2021; Prigione and Adjaye, 2010; Vantaggiato et al., 2019; Kraus et al., 2021). The connection between alterations in peroxisomal fission and metabolic changes associated with cellular differentiation remains less clear. Here, we provide an overview of the functional and regulatory aspects of the mitochondrial and peroxisomal fission machinery and provide insight into the current mechanistic understanding by which mitochondrial and peroxisomal fission influence neurogenesis.
    Keywords:  Brain; DRP1; Metabolism; Mitochondria; Neurons; Peroxisomes
    DOI:  https://doi.org/10.1016/j.biocel.2025.106774
  6. Res Sq. 2025 Mar 19. pii: rs.3.rs-6010379. [Epub ahead of print]
    Molecular elucidation of brain lipofuscin in aging and Neuronal Ceroid Lipofuscinosis.
    Sreeganga Chandra, Sofia Tieze, Alexander Esq, Rachel McAllister, Matija Lagator, Betül Yücel, Eric Sun, TuKiet Lam, Nicholas Lockyer, Kallol Gupta.
      Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition and report the spatiotemporal dynamics of lipofuscin accumulation in aging and NCL on a neuroanatomical atlas. Multimodal mass spectrometry, ultrastructural analyses, and assays of metabolic flux identify a primary role of the lysosomal-mitochondrial axis in lipofuscin formation. Dissection of implicated molecular pathways reveals protein S-acylation and lipid homeostasis as central processes involved in aging and NCL.
    DOI:  https://doi.org/10.21203/rs.3.rs-6010379/v1
  7. Cell. 2025 Mar 26. pii: S0092-8674(25)00270-3. [Epub ahead of print]
    Cell membranes sustain phospholipid imbalance via cholesterol asymmetry.
    Milka Doktorova, Jessica L Symons, Xiaoxuan Zhang, Hong-Yin Wang, Jan Schlegel, Joseph H Lorent, Frederick A Heberle, Erdinc Sezgin, Edward Lyman, Kandice R Levental, Ilya Levental.
      Membranes are molecular interfaces that compartmentalize cells to control the flow of nutrients and information. These functions are facilitated by diverse collections of lipids, nearly all of which are distributed asymmetrically between the two bilayer leaflets. Most models of biomembrane structure and function include the implicit assumption that these leaflets have similar abundances of phospholipids. Here, we show that this assumption is generally invalid and investigate the consequences of lipid abundance imbalances in mammalian plasma membranes (PMs). Using lipidomics, we report that cytoplasmic leaflets of human erythrocyte membranes have >50% overabundance of phospholipids compared with exoplasmic leaflets. This imbalance is enabled by an asymmetric interleaflet distribution of cholesterol, which regulates cellular cholesterol homeostasis. These features produce unique functional characteristics, including low PM permeability and resting tension in the cytoplasmic leaflet that regulates protein localization.
    Keywords:  cholesterol; lipid asymmetry; lipid diffusion; membrane packing; membrane structure; peripheral protein; permeability; phospholipid; plasma membrane; protein-membrane interactions
    DOI:  https://doi.org/10.1016/j.cell.2025.02.034
  8. J Lipid Res. 2025 Mar 27. pii: S0022-2275(25)00047-1. [Epub ahead of print] 100787
    Associations between plasma 24(S)-Hydroxycholesterol and neuropsychological profile in Fragile X Syndrome.
    Asma Laroui, Daniela Rojas, Sophie Bouhour, Mélodie Proteau-Lemieux, Luc Galarneau, Sérine Benachenhou, Armita Abolghasemi, Rosalie Plantefeve, Pierre-Luc Mallet, François Corbin, Jean-François Lepage, Artuela Çaku.
      Fragile X Syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 gene, characterized by low plasma cholesterol levels. Considering the essential role of brain cholesterol in signaling and synaptogenesis, it is important to screen for brain cholesterol abnormalities in FXS and explore their link with neuropsychological profiles. Brain cholesterol is synthesized in situ, and the excess is primarily converted to 24(S)-hydroxycholesterol (24(S)-OHC). 27-hydroxycholesterol (27-OHC) is the major cholesterol oxidation metabolite that crosses the blood-brain barrier from peripheral circulation into the brain Plasma levels of 24(S)-OHC and 27-OHC were quantified in FXS and control individuals. The FXS group underwent transcranial magnetic stimulation to evaluate corticospinal excitability and inhibition. The clinical profile was assessed using questionnaires evaluating specific symptoms related to autism, aberrant behaviors, and anxiety. Study results show a significant decrease in plasma levels of 24(S)-OHC in FXS as compared to controls (78.48 nM ± 20.90 vs 99.53 nM ± 32.30; p = 0.006). Moreover, a negative correlation was observed between plasma levels of 24(S)-OHC and Motor-Evoked Potential (rs = -0.57; p = 0.05) in FXS. Similarly, a negative correlation was also found between plasma levels of 24(S)-OHC and the total score of the Social Communication Questionnaire (rs = - 0.72; p = 0.002) and the Anxiety Depression and Mood Scale (rs = - 0.61; p = 0.02). The 24(S)-OHC is associated with specific neurophysiological and behavioral characteristics in individuals with FXS. Larger studies are warranted to confirm the potential of 24(S)-OHC as a reliable biomarker for FXS.
    Keywords:  24(S)-OHC; 27-OHC; Cholesterol; Clinical profile; FMR1; FXS; Transcranial magnetic stimulation; oxysterols
    DOI:  https://doi.org/10.1016/j.jlr.2025.100787
  9. Neurobiol Dis. 2025 Mar 27. pii: S0969-9961(25)00105-6. [Epub ahead of print]209 106889
    α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
    Yakum B Mingo, Martha L Escobar Galvis, Michael X Henderson.
      Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.
    Keywords:  Cell death; Mitochondrial complex I; PINK1; Parkin; mtDNA; α-Synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2025.106889
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