Mol Brain [JOURNAL]
Sun
200 papers
Intranasal administration of human mesenchymal stromal cell-derived small extracellular vesicles delays disease progression in the SOD1(G93A) mouse model.
Hirota R, Lankford KL, Nakazaki M … +2 more , Toyoshima M, Kocsis JD
Mol Brain · 2026 Mar · PMID 41776544 · Full text
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been repo...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, with no established disease-modifying therapy. Mesenchymal stem/stromal cells (MSCs) have been reported to exert neuroprotective effects in models of injury and disease, acting primarily through release of small extracellular vesicles (sEVs). MSC-derived sEVs (MSC-sEVs) have therefore attracted attention as a potential cell-free therapeutic approach for treating neurological conditions such as ALS. Because MSC-sEVs can cross both the nasal epithelial barrier and blood-brain barrier to reach the central nervous system (CNS), intranasal administration represents an attractive approach for repeated delivery of MSC-sEVs for long-term administration. In this study, we administered bone marrow-derived MSC-sEVs or vehicle intranasally to a SOD1(G93A) transgenic mouse model of ALS; the large majority of the sEVs had surface markers for exosomes. Dosing was for three consecutive days per week beginning one day after onset of neurological symptoms and continuing until a moribund state. Neurological score and body weight were recorded daily. Although total survival time and post-onset survival duration were not significantly prolonged by MSC-sEV treatment, MSC-sEV treatment significantly delayed progression from a mild symptom phase (NeuroScore 1) to more severe symptoms (NeuroScore 2) compared with vehicle-treated controls and showed a trend toward slower weight loss. These findings indicate that intranasal administration of MSC-sEVs can delay functional deterioration and prolong the mild impairment stage in an ALS mouse model. If translatable to human patients, such preservation of neurological function could represent a clinically meaningful outcome.
Recapitulating Alzheimer's disease pathophysiology with a microfluidic neurospheroid-grafted endothelial barrier model.
Uzoechi SC, Johnson-Campbell C, Badeaux CJ … +3 more , Kwak SS, Kim DY, Yun Y
Mol Brain · 2026 Mar · PMID 41776543 · Full text
BACKGROUND: Traditional two-dimensional (2D) models do not adequately capture the complex cellular interactions, brain-specific architecture, and progressive pathology of Alzheimer's disease (AD). Three-dimensional (3D)...
BACKGROUND: Traditional two-dimensional (2D) models do not adequately capture the complex cellular interactions, brain-specific architecture, and progressive pathology of Alzheimer's disease (AD). Three-dimensional (3D) organoid and microfluidic technologies provide more physiologically relevant platforms for studying AD-associated neurovascular dysfunction. METHODS: We developed a membrane-free microfluidic endothelial barrier model integrated with neurospheroids derived from familial AD (FAD) neural progenitor cells. Human endothelial cells were cultured within perfusable microfluidic channels to establish a vascular-like interface rather than a fully specialized BBB endothelium. Pre-differentiated neurospheroids were grafted into the brain chamber. Endothelial barrier integrity, tight-junction expression, phosphorylated tau (pTau), and Aβ42/Aβ40 production and distribution between compartments were assessed using immunofluorescence imaging and ELISA. RESULTS: The neurospheroid-grafted endothelial barrier construct captured key AD-associated phenotypes. ReN-AD-D4 models exhibited increased endothelial barrier permeability, reduced ZO-1 expression, and elevated pTau relative to controls. The platform supported endogenous Aβ generation, accumulation, and endothelial-associated deposition at the endothelial barrier. ELISA demonstrated differential Aβ42 and Aβ40 distribution, consistent with isoform-selective behavior reported in AD pathology. Collectively, these results indicate co-occurring neuronal and endothelial barrier alterations within the integrated 3D system. CONCLUSION: This microfluidic endothelial barrier-neurospheroid platform enables quantitative assessment of amyloid-β accumulation, spatial distribution, and compartmentalized secretion alongside tau pathology and endothelial barrier integrity changes. Integrating human endothelial monolayers with FAD-derived neurospheroids, the system is scalable and compatible with high-content imaging. Although it does not model BBB-specific transport mechanisms, it provides a robust framework for hypothesis-driven studies of neurovascular interactions and therapeutic screening applications.
Bridging neurobiological mechanisms and translational applications in cognitive science: inspirations from the MCCS-NYUAD meeting 2025.
Nami M, Wang DO, MCCS-NYUAD Panel
Mol Brain · 2026 Feb · PMID 41772596 · Full text
The Molecular and Cellular Cognition Society (MCCS) Meeting (NYU Abu Dhabi, February 17-18th, 2025) brought together leading experts in neuroscience to present breakthroughs addressing the molecular and neuronal mechanis...
The Molecular and Cellular Cognition Society (MCCS) Meeting (NYU Abu Dhabi, February 17-18th, 2025) brought together leading experts in neuroscience to present breakthroughs addressing the molecular and neuronal mechanisms underlying cognition, emotion, and behavior. This review is inspired by the meeting, which emphasized emerging molecular and cellular mechanisms including epigenetic regulation of memory, dynamic engram synapse formation, synaptic epitranscriptomics, metaplasticity, and metabolomic-neuroimmune interactions. Learning and cognition have increasingly become focal points within broader advances in neuroimaging innovations, high-throughput molecular diagnostics, and computational modeling geared toward precision neurodiagnostics and personalized neurocognitive therapeutics. The meeting also scrutinized how stress, circadian rhythm disruption, and neuroinflammation converge to shape cognitive resilience and dictate dysregulated attention and learning mechanisms underlying cognitive dysfunction. Such conditions span neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Collectively, the studies highlighted how experience-dependent synaptic and circuit-level changes influence cognition, sensory integration, and motor output. Further discussions addressed the translational implications of these findings, including their potential to advance neurotechnologies such as targeted neuromodulation, pharmacogenomic interventions, and AI-based biomarker discovery. Drawing on the scientific discussions at the MCCS-NYUAD meeting, we synthesize a research roadmap for the future of precision neurocognitive medicine by integrating molecular cognition with clinical neuroscience. Future research priorities include bridging gaps in molecular biomarkers of neurocognitive aging and leveraging AI-driven neurodiagnostics and large-scale biological data analytics. Overall, the meeting laid the groundwork for a shift in neuroscience toward linking mechanistic understanding with clinical relevance to enhance cognitive health and develop targeted neurotherapeutic approaches.
CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.
Barnie PA, Pomeyie K, Amoani B … +5 more , Kyei F, Mumuni AU, Afrifa J, Essien-Baidoo S, Boison D
Mol Brain · 2026 Feb · PMID 41742223 · Full text
Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenera...
Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.
Early hypoxia-induced secretome remodeling reveals adaptive mechanisms and biomarkers of blood-brain barrier dysfunction in ischemic stroke.
Wu Q, Jiang Y, Peng L … +3 more , Dang Y, You C, Li X
Mol Brain · 2026 Feb · PMID 41699623 · Full text
Reversible disruption of the blood-brain barrier (BBB) occurs within hours after the onset of ischemic stroke (IS), offering a critical window for therapeutic intervention. However, the molecular characteristics and thei...
Reversible disruption of the blood-brain barrier (BBB) occurs within hours after the onset of ischemic stroke (IS), offering a critical window for therapeutic intervention. However, the molecular characteristics and their potential as circulating biomarkers associated with this transient phase of BBB dysfunction remain poorly defined. To elucidate these mechanisms, we employed an oxygen-glucose deprivation (OGD) model in human cerebral microvascular endothelial cells (hCMEC/D3) to simulate early ischemic stress, and systematically profiled their secreted proteome and metabolome. By comparing with non-brain-derived human umbilical vein endothelial cells (HUVECs), we identified brain endothelium-specific hypoxic response signatures. These molecules were significantly enriched in pathways related to metabolic reprogramming, antioxidant defense, and epigenetic regulation pathways, indicating a coordinated adaptive response to preserve BBB homeostasis. Furthermore, integrative multi-omics analysis revealed 14 protein-metabolite pairs with potential functional synergy. Based on a multi-criteria screening strategy including brain specificity, functional relevance, and secretory potential, we prioritized 10 candidate circulating biomarkers: ALDH2, ITGA5, KYNU, TFRC, CD44, COL1A2, HEXB, HSPG2, THBS4, and DLD. Preliminary validation using serum from acute IS (AIS) patients and healthy controls showed significantly altered levels of ALDH2, ITGA5, KYNU, and TFRC, with TFRC exhibiting promising diagnostic performance both individually (AUC = 0.816) and in combination with the other three biomarkers (AUC = 0.876). Moreover, multivariate logistic regression analysis revealed that elevated TFRC was independently associated with poor 90-day outcomes (OR = 1.02, 95% CI 1.00-1.04, P = 0.031), while higher DLD levels were correlated with good prognosis (OR = 0.68, 95% CI 0.39-0.90, P = 0.047). Notably, TFRC expression was upregulated in hCMEC/D3 cells under early hypoxic stress, while its extracellular secretion was reduced. This observation suggests a potential early cellular adaptation to preserve iron homeostasis. In summary, these findings uncover early molecular adaptations of brain microvascular endothelial cells to ischemic stress and propose a panel of secreted biomarkers with translational potential for early diagnosis and outcome prediction in IS, potentially guiding the development of time-sensitive therapeutic strategies.
Crosstalk of KCNH1 and KCNH5 gain-of-function mutations leading to epilepsy and neurodevelopmental disorders.
Bernert A, Rühl P, Schönherr R … +1 more , Heinemann SH
Mol Brain · 2026 Feb · PMID 41656275 · Full text
Voltage-gated K (Kv) channels are tetrameric complexes of proteins encoded by KCN genes. Gain-of-function (GoF) mutations in KCNH1 (Kv10.1, hEAG1) and KCNH5 (Kv10.2, hEAG2) give rise to developmental disorders, intellect...
Voltage-gated K (Kv) channels are tetrameric complexes of proteins encoded by KCN genes. Gain-of-function (GoF) mutations in KCNH1 (Kv10.1, hEAG1) and KCNH5 (Kv10.2, hEAG2) give rise to developmental disorders, intellectual disability, and epilepsy. Currently, clinical symptoms are not straightforwardly associated with functional properties of mutated channels. Here we investigated how members of the KCNH subfamily are affected by heteromerization with mutant Kv10.1 or Kv10.2 protein subunits. The de novo variant Kv10.1-G496E, which leads to impaired neurodevelopment and epilepsy, was expressed alone or with other wild-type subunits in HEK293T cells and characterized using whole-cell patch clamp. While Kv10.1-G496E alone did not yield functional K channels, coexpression with Kv10.1 or Kv10.2 shifted the half-maximum voltage of activation in the hyperpolarizing direction. Likewise, the homologous mutation Kv10.2-G465E did not yield functional channels but also induced GoF upon coexpression with wild-type Kv10.1 or Kv10.2. By contrast, the mutants did not affect the function of Kv11.1 (KCNH2, hERG1) channels. To infer the relevance of Kv10 GoF mutations under physiological conditions, we used the fluorescent genetically encoded voltage indicator mK2-rEstus and found that both, Kv10.1 and Kv10.2, hyperpolarized HEK293T cells, and that coexpression of the GoF mutants augmented this hyperpolarization. Our findings imply that interpretation of clinical symptoms related to Kv10 GoF mutations requires considering the functional crosstalk with Kv10.1 and Kv10.2 subunits, which are both expressed in glutamatergic neurons in cortical Layers III and IV.
Chronic stress increases the susceptibility to chronic vulvar pain following acute vulvar inflammation in a preclinical model of vulvodynia.
Awad-Igbaria Y, Abu-Ata S, Jabarin R … +7 more , Sakas R, Igbaria L, Hamdan AN, Lowenstein L, Bornstein J, Palzur E, Shamir A
Mol Brain · 2026 Feb · PMID 41654975 · Full text
Psychological distress and chronic stress were suggested to contribute to the pathophysiology of idiopathic pain conditions such as provoked vulvodynia (PV). The comorbidity of PV and mood disorder is quite common. Thus,...
Psychological distress and chronic stress were suggested to contribute to the pathophysiology of idiopathic pain conditions such as provoked vulvodynia (PV). The comorbidity of PV and mood disorder is quite common. Thus, vulvar pain can trigger anxiety, and mood disruption, whereas elevated anxiety and mood disruption play a critical role in pain maintenance. Yet, whether chronic stress can facilitate the development of chronic vulvar pain remains unclear. Here, we aimed to assess the effects of chronic stress on anxiety, depression-like behaviors, and the development of chronic vulvar pain after vulvar inflammation, which combines acute inflammation with chronic unpredictable stress (CUS) in female rats. Current result indicates that CUS leads to a reduction in vulvar mechanical thresholds and an increase in anxiety-like behavior, including reduced entries and time spent in the open arms of the EPM, reduced time in the center, increased distance moved in the OF, and reduced sucrose intake compared to the non-CUS group. Blood corticosterone levels and gene expression related to neuronal activation (cFOS) and GABA-synthesis (GAD67) were significantly increased in the amygdala and PAG in the CUS group compared to the non-CUS group. Following vulvar injection (saline/zymosan), there was a significant reduction in vulvar mechanical threshold in all groups: non-CUS/Saline, non-CUS/Zymosan, CUS/Saline, and CUS/Zymosan. However, mechanical thresholds returned to baseline in all groups except the CUS/Zymosan group, which exhibited prolonged vulvar hypersensitivity with no sign of recovery. Long-term behavioral assessments revealed reduced open-arm entries, altered locomotion, and decreased sucrose intake of the CUS groups compared to non-CUS groups. In conclusion, chronic stress enhances vulnerability to chronic vulvar pain following acute inflammation, alongside persistent anxiety and depression-like behaviors. These findings support a biopsychosocial model of PV, emphasizing the interplay between stress and inflammation in vulvar pain chronification.
Impairment of novelty-dependent hippocampal behavioural tagging in Septin5-deficient mice.
Ageta-Ishihara N, Fukumasu N, Fujii K … +8 more , Koshidaka Y, Tanigaki K, Hiramoto T, Kang G, Hiroi N, Miyakawa T, Takao K, Kinoshita M
Mol Brain · 2026 Feb · PMID 41634751 · Full text
Septin-5 is a GTP-binding protein implicated in synaptic vesicle exocytosis and 22q11.2 deletion-related neuropsychiatric disorders. We recently showed that Septin5-deficient (Septin5) mice display intact hippocampal spi...
Septin-5 is a GTP-binding protein implicated in synaptic vesicle exocytosis and 22q11.2 deletion-related neuropsychiatric disorders. We recently showed that Septin5-deficient (Septin5) mice display intact hippocampal spine ultrastructure, but marked deficits in both recent and remote contextual fear memory, whereas cued fear memory is preserved. Building on these findings, we asked whether Septin-5 is required for baseline forms of hippocampus-dependent spatial and object recognition memories, or more selectively for novelty-dependent memory stabilization. Using congenic Septin5 mice, we performed a behavioural test battery including hippocampus-dependent spatial and object recognition tasks. Septin5 mice showed normal performance in T-maze (spontaneous and forced alternation), Barnes maze (acquisition and recent/remote spatial reference memory), and object location memory. After 5-min training in the novel object recognition task, short-term recognition memory was indistinguishable between genotypes. Together with our previous report that long-term object recognition after 15-min training is intact in Septin5 mice, these results indicate that Septin-5 is dispensable for a broad set of hippocampus-dependent spatial and object recognition memories despite contextual fear deficits. In contrast, Septin5 mice exhibited a selective deficit in behavioural tagging: in wild-type mice, novelty exploration 30 min after 5-min object training converted an otherwise labile trace into a 24-h memory, whereas this novelty-induced stabilization was absent in Septin5 mice. Thus, Septin-5 is not required for baseline performance in hippocampus-dependent spatial and object recognition tasks, but is implicated in novelty-dependent stabilization of weak hippocampal memories under the established 10-min novelty exposure condition, consistent with a contribution to synaptic tagging-like processes.
The role of TRPV4 in ischemic stroke.
Guo J, Yu X, Ma Y
Mol Brain · 2026 Jan · PMID 41606676 · Full text
Recent advances in mechanotransduction research have highlighted the important role of mechanosensitive ion channels, particularly the transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4, a non-selective cati...
Recent advances in mechanotransduction research have highlighted the important role of mechanosensitive ion channels, particularly the transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4, a non-selective cation channel predominantly located on the plasma membrane, is widely expressed in the mammalian and human brain and exhibits sensitivity to mechanical stimuli due to its unique structural features. Emerging evidence suggests that TRPV4 may function as a modulator in the pathophysiology of ischemic stroke. During the acute phase of stroke, TRPV4 activation has been linked to neuronal injury and cerebral edema. In contrast, during the recovery phase following ischemia-reperfusion, TRPV4 appears to contribute to neurovascular remodeling by facilitating intracranial arterial dilation and collateral vessel formation. These phase-dependent roles indicate that targeted modulation of TRPV4, particularly through physical therapies, could represent a potential therapeutic strategy to improve outcomes after ischemic stroke. This review summarizes current findings on TRPV4 in stroke pathobiology and discusses its potential as a mechanotherapeutic target.
Insights into the interplay between stroke and depression through lipid metabolism-related diagnostic genes.
Liu Y, Chen B, Yang Y … +6 more , Li Y, Xia X, Yan K, Xu H, Li Y, Tan X
Mol Brain · 2026 Jan · PMID 41547864 · Full text
Stroke, a result of acute cerebrovascular disease that causes cerebral dysfunction, often coexists with depression or even major depressive disorder (MDD). Despite the recognized significance of lipid metabolism disorder...
Stroke, a result of acute cerebrovascular disease that causes cerebral dysfunction, often coexists with depression or even major depressive disorder (MDD). Despite the recognized significance of lipid metabolism disorders in both stroke and depression, their interwoven role in the pathogenesis of these conditions remains largely uncharted. This study sourced transcriptomic data linked to stroke and depression from the GEO database. Hub genes were identified through weighted gene coexpression network analysis (WGCNA) and machine learning algorithms. The diagnostic efficacy of the model featuring hub genes was evaluated using receiver operating characteristic (ROC) curve analyses and nomogram plots. Enrichment analysis and immune infiltration were examined while potential therapeutic agents were predicted using the drug profile database. The expression levels of the hub genes were verified on peripheral blood samples using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). 6 differentially expressed genes (DEGs) related to lipid metabolism were identified showing significant enrichment in metabolic and immune pathways. The diagnostic model constructed based on these genes demonstrated robust performance across multiple datasets. Gene set enrichment analysis (GSEA) suggested the involvement of nucleic acid metabolism and olfactory transduction in both diseases. Immune infiltration analysis revealed significant differences among various immune cells, such as monocytes and neutrophils. 11 potential drugs targeting at least two hub genes were identified. The exploration of lipid metabolism-related diagnostic genes offers valuable insights into the potential interplay between stroke and depression.
TMEM16A ablation in cholinergic medial habenula neurons induces early-onset schizophrenia-like phenotypes in mice.
Kim A, Lee S, Lee S … +4 more , Kim J, Im HI, Park JY, Hwang EM
Mol Brain · 2026 Jan · PMID 41527097 · Full text
Schizophrenia is a heterogeneous psychiatric disorder that remains inadequately treated with current therapies. Developing appropriate animal models that reflect the broad spectrum of schizophrenia symptoms is crucial fo...
Schizophrenia is a heterogeneous psychiatric disorder that remains inadequately treated with current therapies. Developing appropriate animal models that reflect the broad spectrum of schizophrenia symptoms is crucial for advancing our understanding of the disease and identifying effective treatments. However, existing animal models often have limitations in fully recapitulating the diverse symptomatology observed in humans. Previously, we reported that mice with conditional ablation of TMEM16A (ANO1) in cholinergic neurons of the medial habenula (ANO1 cKO) exhibit behavioral patterns indicative of anxiety, reduced social motivation, and anhedonia. In the present study, we found that these mice display schizophrenia-like phenotypes, including impaired prepulse inhibition (PPI), enhanced cocaine sensitivity, and reduced c-Fos expression in the medial prefrontal cortex (mPFC), a feature also observed in patients with schizophrenia. Moreover, ANO1 cKO mice exhibited elevated Drd2 expression in the ventral medial geniculate nucleus (MGv) and transcriptomic alterations overlapping with schizophrenia-associated genes. Importantly, these phenotypes emerged only when ANO1 deletion occurred during development, whereas adult-stage manipulation failed to reproduce them, underscoring a critical developmental window for habenular-thalamocortical circuit maturation. This developmental specificity represents a central novelty of the model and provides new insight into how early-life dysregulation of habenular cholinergic signaling contributes to schizophrenia-related pathophysiology.
Mycophenolate mofetil reduces the branching of microglial processes.
Teruya RI, Ueda K, Taketomi T … +4 more , Yamamoto T, Yamashita N, Konno H, Tsuruta F
Mol Brain · 2026 Jan · PMID 41521301 · Full text
Microglia, the resident immune cells in the central nervous system, play important roles not only in immune response but also in neurogenesis, synaptogenesis, and neural circuit formation. Microglia also surveil the brai...
Microglia, the resident immune cells in the central nervous system, play important roles not only in immune response but also in neurogenesis, synaptogenesis, and neural circuit formation. Microglia also surveil the brain environment via elongation and retraction of their processes. Previously, we found that the purine salvage pathway is involved in the regulation of morphology and dynamics of the microglial cell line BV2. Here, we show that intraperitoneal administration of mycophenolate mofetil (MMF), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, reduces microglial branching during postnatal development. Imaging mass spectrometry analysis revealed that MMF administration decreases guanosine nucleotides in the brain. Interestingly, despite the essential role of guanosine nucleotides in cellular proliferation, MMF administration did not significantly affect microglial proliferation. On the other hand, MMF administration attenuated the level of GTP-bound forms of RhoA and Rac1 small GTPases. Notably, MMF administration decreased the number of branches, while process length remained unaffected. Since microglial branching affects microglial complexity and diversity, our findings suggest that guanosine nucleotide production is essential for generating proper microglial diversity.
Primary cortical neurons precipitate and extrude large mitochondria-associated calcium-phosphate sheets with a bone-precursor-like ultrastructure.
Anderson ED, Cronkite CA, Baldwin PR … +6 more , Abella CP, Duman JG, Simmonds AN, Waxham MN, Tolias KF, Ludtke SJ
Mol Brain · 2026 Jan · PMID 41508094 · Full text
Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzhei...
Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzheimer's disease and Leigh syndrome. The nexus of pathologic extracellular CaP in the nervous system is not well understood, but prior evidence suggests mitochondria could be a source. We have observed mitochondria-sized sheet-like CaP aggregates within functional wild type cortical neuron cultures at 1 and 20 days in vitro. Neurons were extracted from embryonic day 18 (E18) rat embryos following standard protocols to study neuronal structure and function. We have used a combination of cryo-ET, cryo-CLEM, and LDSAED to demonstrate that these aggregates are octacalcium phosphate-like, are associated with mitochondria, and that at least a portion are extruded via migrasomes. Visually similar aggregates were previously observed in Huntington's disease model neurons, but in that study they were not observed in WT controls. These findings show that this CaP aggregation process occurs routinely in WT neurons and may reveal an important link for how mitochondria may participate in calcification, highlighting them as potential therapeutic targets in neurological disorders characterized by pathological calcification, such as Alzheimer's disease.
Proteasome inhibition by VR23 enhances autophagic clearance of FUS-mediated persistent stress granule in SH-SY5Y cells.
Kim SH, So JH, Kim YH … +8 more , Kim HS, Park NY, Kim JB, Jo DS, Yeom E, Lee JA, Bae JE, Cho DH
Mol Brain · 2026 Jan · PMID 41508039 · Full text
Autophagy is a conserved catabolic pathway that preserves cellular homeostasis through lysosomal degradation. Beyond its general role in proteostasis, selective autophagy mediates the clearance of selective cellular targ...
Autophagy is a conserved catabolic pathway that preserves cellular homeostasis through lysosomal degradation. Beyond its general role in proteostasis, selective autophagy mediates the clearance of selective cellular targets such as persistent stress granules (SGs), in a process termed granulophagy. SGs are dynamic cytoplasmic assemblies that normally disassemble after stress relief; however, their aberrant persistence has arisen as a pathological feature of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, the molecular regulation of granulophagy remains incompletely understood. Here, we established a tandem fluorescent SG reporter system with mCherry-pHluorin-FUS, enabling live-cell visualization of granulophagic flux. Using this system, we screened a chemical library and identified VR23, a proteasome inhibitor, as a potent inducer of granulophagy. VR23 promoted SG clearance through autophagic mechanisms, as evidenced by enhanced LC3 colocalization, lysosome-dependent degradation, and Bafilomycin A1-sensitive flux. Notably, disruption of SG assembly via G3BP1 inhibition abolished VR23-induced clearance, confirming its SG selectivity. These findings suggest a link between proteasome inhibition and granulophagy, highlighting VR23 as a valuable tool compound to dissect the mechanisms of SG turnover, and provide a platform for discovering modulators of pathological SG clearance in protein aggregation.
Mosaic AAV mediates efficient transduction across the central and peripheral nervous systems.
Jiang M, Yin W, Mo X … +3 more , Wang Z, Qiu M, Dai ZM
Mol Brain · 2025 Dec · PMID 41457284 · Full text
Adeno-associated virus (AAV) is a promising vector for neurological gene therapy, yet engineered serotypes are restricted to targeting either the central or peripheral nervous system (CNS or PNS). To overcome this limita...
Adeno-associated virus (AAV) is a promising vector for neurological gene therapy, yet engineered serotypes are restricted to targeting either the central or peripheral nervous system (CNS or PNS). To overcome this limitation, we generated AAV with mosaic capsid, AAV-PHP.(S + eB), by co-packaging the AAV with two engineered capsid variants: AAV-PHP.eB and AAV-PHP.S, which exhibits strong CNS tropism and PNS tropism, respectively. Systemic administration of AAV-PHP.(S + eB) in adult mice mediated widespread transgene expression throughout the CNS, comparable to AAV-PHP.eB, while simultaneously achieving robust transduction of dorsal root ganglia neurons, similar to AAV-PHP.S. Notably, the mosaic vector demonstrated significantly reduced off-target transduction in the liver compared to both parental vectors, suggesting an improved safety. These results indicate that mosaic capsid assembly is a potent strategy for designing dual-tropic AAV vectors without increasing viral dose. This approach holds significant promise for treating complex neurological disorders that involve both nervous system compartments.
Early autism detection: a review of emerging technologies, biomarkers, and explainable AI approaches.
Agrawal R, Agrawal R
Mol Brain · 2025 Dec · PMID 41449406 · Full text
Autism Spectrum Disorder (ASD) presents as a complicated neurodevelopmental disorder which leads to social communication challenges and repetitive behavioral patterns. Early identification of ASD is crucial to facilitate...
Autism Spectrum Disorder (ASD) presents as a complicated neurodevelopmental disorder which leads to social communication challenges and repetitive behavioral patterns. Early identification of ASD is crucial to facilitate early intervention that can make a large positive impact on long-term developmental outcomes. With the advent of artificial intelligence (AI) and data-driven diagnoses, there is increased interest in combining machine learning methods with biological and behavioral signatures to detect early ASD. This review provides an overview of broad classes of biomarkers-behavioral, neuroimaging, genetic, and eye gaze-and their respective methodologies, clinical applications, and diagnostic accuracy. For each of these biomarker domains, the research gap has been identified as existing for instance limited interpretability in neuroimaging models, genomics-related ethical and data accessibility issues, and innovation saturation for behavioral measurement. A comparative analysis highlights eye gaze analysis as a promising but under-explored option, providing a balance of cost-effectiveness, non-invasiveness, and potential for real-time, objective measurement. In addition, the application of Explainable AI (XAI) methodologies across these biomarker fields is discussed in order to meet the pressing need for transparency, clinical confidence, and decision-making support. This review makes a final call for further exploration of eye gaze-based models enriched by XAI methods as a future research direction towards filling the gap between algorithmic innovation and real-world, interpretable diagnostics in the context of ASD research.
Human midbrain organoids reveal the characteristics of axonal mitochondria specific to dopaminergic neurons.
Nishijima A, Yokota M, Kakuta S … +6 more , Yamaguchi A, Ishikawa KI, Okano H, Akamatsu W, Hattori N, Koike M
Mol Brain · 2025 Dec · PMID 41444912 · Full text
Mitochondrial dysfunction and abnormalities in mitochondrial quality control contribute to the development of neurodegenerative diseases. Parkinson's disease is a neurodegenerative disease that causes motor problems main...
Mitochondrial dysfunction and abnormalities in mitochondrial quality control contribute to the development of neurodegenerative diseases. Parkinson's disease is a neurodegenerative disease that causes motor problems mainly due to the loss of dopaminergic neurons in the substantia nigra pars compacta. Axonal mitochondria in neurons reportedly differ in properties and morphologies from mitochondria in somata or dendrites. However, the function and morphology of axonal mitochondria in human dopaminergic neurons remain poorly understood. To define the function and morphology of axonal mitochondria in human dopaminergic neurons, we newly generated tyrosine hydroxylase (TH) reporter (TH-GFP) induced pluripotent stem cell (iPSC) lines from one control and one PRKN-mutant patient iPSC lines and differentiated these iPSC lines into dopaminergic neurons in two-dimensional monolayer cultures or three-dimensional midbrain organoids. Immunostainings with antibodies against axonal and dendritic markers showed that axons could be better distinguished from dendrites of dopaminergic neurons in the peripheral area of three-dimensional midbrain organoids than in two-dimensional monolayers. Live-cell imaging and correlative light-electron microscopy in peripheral areas of midbrain organoids derived from control TH-GFP iPSCs demonstrated that axonal mitochondria in dopaminergic neurons had lower membrane potential and were shorter in length than those in non-dopaminergic neurons. Although the mitochondrial membrane potential did not significantly differ between dopaminergic and non-dopaminergic neurons derived from PRKN-mutant patient lines, these differences tended to be similar to those in control lines. These results were also largely consistent with those of our previous study on somatic mitochondria. The findings of the present study indicate that midbrain organoids are an effective tool to distinguish axonal from dendritic mitochondria in dopaminergic neurons. This may facilitate the analysis of axonal mitochondria to provide further insights into the mechanisms of dopaminergic neuron degeneration in patients with Parkinson's disease.
Sleep transcends limited knowledge to support logical reward-related decisions in a novel task in male mice.
Fayed MR, Ghandour K, Choucry A … +2 more , Abdou K, Inokuchi K
Mol Brain · 2025 Dec · PMID 41388418 · Full text
Sleep is essential for strengthening memory and consolidation. Emerging evidence supports its role in cognitive processes such as rule abstraction and inference. However, how sleep influences logical nongambling probabil...
Sleep is essential for strengthening memory and consolidation. Emerging evidence supports its role in cognitive processes such as rule abstraction and inference. However, how sleep influences logical nongambling probabilistic decision-making has yet to be discovered. We developed a reward-based logical decision task that requires rule use and allows scope for reasoning. The mice were able to discriminate between two contexts with different outcomes. This behavior paradigm teaches mice to make free choices between an option to obtain a high-value probabilistic reward in specific entries and a guaranteed safe, low-value option. This knowledge was acquired through six forced entries to each side in training sessions, and they were then tested on subsequent days. As a hidden rule, they may extend their knowledge during these testing sessions by being allowed to take extra entries. We found that extended sleep deprivation disrupted their logical decisions. Sleep-deprived mice were unable to maintain their previous logical performance, resulting in a significant reduction in the rewards they earned. Rule switching in an updated version of the task eliminated gambling-like behavioral dependence in this novel task. These results suggest that adequate sleep is necessary for applying learned knowledge and engaging in complex cognitive functions, such as reasoning.
Identification and validation of microglia-associated genes in ischemic stroke using single-cell and bulk RNA-seq.
Qian D, Lu S, Hu Y … +2 more , Leng B, Qin X
Mol Brain · 2025 Dec · PMID 41354822 · Full text
Ischemic stroke (IS) is an acute cerebrovascular disease characterized by high incidence and mortality. The mechanism of microglia in the pathogenesis of IS remains unclear. This study aimed to explore the key genes rela...
Ischemic stroke (IS) is an acute cerebrovascular disease characterized by high incidence and mortality. The mechanism of microglia in the pathogenesis of IS remains unclear. This study aimed to explore the key genes related to microglia in IS and their molecular mechanisms in the pathogenesis. In this study, the transcriptome data of IS were retrieved from public databases. Subsequently, candidate genes were identified through the intersection of microglia-related genes (MGGs) obtained via single-cell annotation and high-dimensional weighted gene co-expression network analysis (hdWGCNA) with differentially expressed genes (DEGs). Next, key genes were determined through protein-protein interaction (PPI) analysis and verification of expression levels. Afterwards, enrichment analysis, variation analysis, construction of regulatory networks, drug prediction, and molecular docking were performed to evaluate the role of key genes in the pathogenesis of IS. Ultimately, the quantitative real-time PCR (qRT-PCR) was applied to confirm the expression levels of DEGs in brain tissues between sham and transient middle cerebral artery occlusion (tMCAO) mice. A total of 1407 DEGs intersected with 100 MGGs, yielding 51 candidate genes. Subsequently, 3 key genes (Cd14, Csf1, and Tlr2) were successfully obtained. The study revealed that these 3 key genes were co-enriched in 4 pathways, such as leishmania infection and ribosomal, and there were differences in the enriched pathways among groups. Notably, the expression of the 3 key genes was regulated by multiple factors, including 32 microRNAs (miRNAs), such as mmu-miR-3072-5p and mmu-miR-3970, and 7 transcription factors (TFs), such as Sp1 and Nfkb1. Meanwhile, these 3 key genes predicted 8 common drugs. Interestingly, Tlr2 and Adapalene exhibited a strong binding affinity (- 9.73 kcal/mol). qRT-PCR analysis revealed significantly elevated mRNA expression levels of Cd14, Csf1, and Tlr2 in tMCAO mice compared to sham-operated controls (p < 0.01). This study identified and validated 3 key genes (Cd14, Csf1, and Tlr2) associated with IS, which may serve as novel targets for IS diagnosis and treatment strategies.
A cross-tissue transcriptome-wide association study identifies novel candidate genes associated with brain glymphatic system function.
Zhu X, Wang S, Zhang S … +4 more , Liu Z, Wang N, Wang S, Yang N
Mol Brain · 2025 Dec · PMID 41351017 · Full text
The glymphatic system plays a key role in brain waste clearance, but its genetic regulation remains poorly understood. Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) index is a non-invasive imagi...
The glymphatic system plays a key role in brain waste clearance, but its genetic regulation remains poorly understood. Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) index is a non-invasive imaging biomarker to asses glymphatic system activity. We integrated mean DTI-ALPS genome-wide association study (GWAS) data from 31,021 individuals of European ancestry with GTEx v8 multi-tissue eQTL data to perform transcriptome-wide association studies (TWAS) using Unified Test for Molecular Signature (UTMOST) and Functional Summary-based Imputation (FUSION). Gene-level associations were further validated by Multi-marker Analysis of Genomic Annotation (MAGMA). Causal inference was conducted using cis-Mendelian randomization (cis-MR) and summary-data-based Mendelian randomization (SMR), while colocalization was applied to provide evidence of strong associations between two traits within a single genetic region, thereby ensuring the stability of the MR conclusions. TWAS identified 17 candidate genes (AGBL5-IT1, CENPA, CGREF1, DNAJC5G, EMILIN1, GCAT, KHK, MAPRE3, OTOF, PLCL1, PREB, RBM43, RFTN2, SERPIND1, SNAP29, TRIOBP, and UCN), among which six protein-coding genes (TRIOBP, MAPRE3, EMILIN1, KHK, GCAT, and CGREF1) were further validated by MAGMA. Cis-MR provided evidence for the causal effects of these six genes, while colocalization supported that the MR conclusions were stable for four of them (TRIOBP, MAPRE3, EMILIN1, and GCAT). Finally, SMR identified three genes (TRIOBP, GCAT, and MAPRE3) that showed consistent and robust associations with DTI-ALPS across multiple tissues. These findings provide statistical evidence for genetic regulation of glymphatic function.
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