Journal Of Neurochemistry[JOURNAL]
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200 papers
Neurons in a Dish: A Review of In Vitro Cell Models for Studying Neurogenesis.
Vassal M, Cruz AC, Rebelo S … +1 more , Martins F
J Neurochem · 2026 Jan · PMID 41517881 · Full text
Understanding neurogenesis, the complex biological process of generating new neurons, is crucial for understanding brain development, function, and potential therapeutic interventions for neurological disorders. Due to t...
Understanding neurogenesis, the complex biological process of generating new neurons, is crucial for understanding brain development, function, and potential therapeutic interventions for neurological disorders. Due to the inherent difficulty of directly observing neurogenesis in the human brain, researchers heavily rely on cell models to simulate this process under controlled conditions. These models serve as invaluable tools to understand the mechanisms underlying the different stages of neurogenesis, helping researchers explore how neurons are generated, mature, and integrate into neural networks, thereby contributing to both normal brain function and neurological disorders. Therefore, this work provides a comprehensive overview of different cell models commonly used in neurogenesis research, from primary cultures and stem cells to immortalized cell lines. This compilation highlights the strengths and limitations of each cell model, which ultimately allows researchers to select the most appropriate model system for their research, thus enhancing the efforts towards unraveling the mysteries of the brain.
The Influence of Blood Brain Barrier Permeability on CSF-To-Serum Ratios of Neurobiomarkers in People With HIV.
Cusato J, Antonucci M, Trunfio M … +7 more , Imperiale D, Vuaran E, Palermiti A, Di Perri G, D'Avolio A, Bonora S, Calcagno A
J Neurochem · 2026 Jan · PMID 41508420 · Publisher ↗
People with HIV (PWH) have a higher risk of central nervous system (CNS) diseases and a timely differential diagnosis may be essential for patient management. Cerebrospinal fluid (CSF) biomarkers have proven effective in...
People with HIV (PWH) have a higher risk of central nervous system (CNS) diseases and a timely differential diagnosis may be essential for patient management. Cerebrospinal fluid (CSF) biomarkers have proven effective in diagnosing neuronal and astrocyte involvement in neurological disorders, but the invasiveness of this method makes it difficult to obtain results; thus, easy-to-obtain matrices (e.g., plasma) have to be analysed. Consequently, the aim of this study was to quantify biomarkers in both serum and CSF with different kits, correlating levels obtained in the two matrices and understanding their impact on blood brain barrier (BBB) permeability. CSF and serum from PWH were analysed through Single Molecule Array (Simoa SR-X, Quanterix). We measured markers of neuronal damage (NfL, tau, ptau), β-amyloid peptides (Aβ and Aβ), signalling and neuronal plasticity (BDNF), astrocyte activation (GFAP), ubiquitin-proteasome involvement (UCH-L1), and programmed death ligand-1 (PD-L1). BBB permeability was assessed through CSF-to-serum albumin ratio (CSAR). We included 286 samples: median age was 42.1 years (30.6-51), 69.2% were male. Median CSAR was 5.4 (3.9-7.3). We observed statistically significant correlations for all serum/CSF pairs, but rho values > 0.5 for tau, p-tau, GFAP, Aβ and Aβ only, when using different kits. NfL CSF-to-plasma ratios were higher in participants with higher CSAR (p = 0.0000016), with a higher ratio in participants with age-adjusted abnormal BBB (n = 34 for intact BBB and n = 66 for altered BBB, p = 0.001). We observed an average-to-high correlation between serum and CSF biomarkers in PWH, suggesting the possible use of serum levels for assessing CNS involvement: it is the first time that BBB permeability was found to influence such correlations.
Brain Glutathione Levels Associate With Cognitive Performance in Older Adults.
Lee P, Erickson KI, Kang C … +12 more , Burns JM, Hillman CH, Kramer AF, Grove G, Vidoni ED, Huang H, McAuley E, Wan L, Oberlin LE, Sutton BP, Marsland AL, Choi IY
J Neurochem · 2026 Jan · PMID 41492778 · Full text
Glutathione (GSH), the brain's primary endogenous antioxidant, is integral to the cerebral antioxidant defense system and essential for maintaining redox homeostasis and neuronal health. Brain GSH levels naturally decrea...
Glutathione (GSH), the brain's primary endogenous antioxidant, is integral to the cerebral antioxidant defense system and essential for maintaining redox homeostasis and neuronal health. Brain GSH levels naturally decrease with age, potentially contributing to cognitive vulnerability through diminished antioxidant capacity. Currently, the relationship between brain GSH and cognitive function in humans remains poorly understood. Using multiple quantum chemical shift imaging, we measured brain GSH levels in 206 cognitively unimpaired older adults (mean age 69.8 ± 3.9 years) and assessed cognitive performance across five core domains: working memory, episodic memory, visuospatial processing, executive function/attentional control, and processing speed. We hypothesized that higher GSH would be associated with better cognitive performance across all five domains, reflecting the putative role of antioxidant capacity in cognitive function. Using multiple regression with age, sex, years of education, and study site as covariates in the model, we found that higher regional brain GSH levels, including frontal and parietal regions, were associated with better working memory (p = 0.008), episodic memory (p = 0.040), and visuospatial processing (p = 0.001), but not with executive function/attentional control or processing speed. These findings highlight the critical neuroprotective role of GSH within the cerebral antioxidant defense system in supporting cognitive health in late adulthood.
Discovery and Characterization of Novel Spirotriazoloquinazolines as Potential Neuroprotectors: Synthesis, Computational Screening, and Preliminary In Vivo Evaluation.
Shabelnyk K, Antypenko L, Bohdan N … +5 more , Ryzhenko V, Belenichev I, Petakh P, Kamyshnyi O, Kovalenko S
J Neurochem · 2026 Jan · PMID 41489256 · Publisher ↗
This study describes the rational design, synthesis, and evaluation of forty 2'-R-6'H-spiro(cycloalkyl/heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines as potential neuroprotective agents targeting multiple receptor syste...
This study describes the rational design, synthesis, and evaluation of forty 2'-R-6'H-spiro(cycloalkyl/heterocyclyl)[1,2,4]triazolo[1,5-c]quinazolines as potential neuroprotective agents targeting multiple receptor systems implicated in cognitive dysfunction. The molecular design integrated structural features from established nootropic and anxiolytic pharmacophores to create compounds with putative multi-target activity. In silico ADMET analyses assessed drug-likeness parameters, while molecular docking studies evaluated binding interactions with nine neuroreceptor targets: glutamate GluA3, GABA(A)R, dopamine D2, serotonin 5-HT1A and 5-HT7, cannabinoid CB2, muscarinic M2 acetylcholine, corticotropin-releasing factor receptor 1 (CRF1R), and metabotropic glutamate receptor 5 (mGluR5). Based on computational predictions, selected compounds underwent preliminary in vivo screening using a ketamine-induced cognitive impairment model in rats. Behavioral assessments examined anxiety-related responses and cognitive performance relative to piracetam and fabomotizole controls. Biochemical analyses measured inflammatory markers (IL-1β, caspase-1), cell survival indicators (Bcl-2), and hypoxic adaptation responses (HIF-1 mRNA). Docking studies indicated favorable binding profiles across tested receptor targets compared to reference ligands, with calculated affinities suggesting potential modulatory interactions. The experiments showed that compounds 25, 26, and 32 attenuated ketamine-induced behavioral alterations, demonstrating effects in anxiety reduction and cognitive performance that appeared numerically greater than piracetam and fabomotizole, though the magnitude and statistical robustness of these differences require further characterization. Compound 31 reduced IL-1β expression by 72% and caspase-1 by 80% relative to ketamine-treated controls. Compound 26 increased Bcl-2 expression by 96% and HIF-1 mRNA levels by 3.5-fold compared to control conditions. These findings suggest that spirotriazoloquinazolines may function as positive modulators at cognitive-enhancing receptors, potentially exerting neuroprotective effects through anti-inflammatory and anti-apoptotic mechanisms. Further investigation is necessary to validate the observed effects, establish dose-response relationships, and elucidate the molecular mechanisms underlying the apparent neuroprotective properties of these compounds.
Essential Roles of Heparan Sulfate Endosulfatase Sulf1 in Reward and Aversion Learning Through Distinct Dopamine D1 and D2 Receptor Pathways in Male Mice.
Miya K, Ohta K, Keino-Masu K … +6 more , Okada T, Mizuno S, Takahashi S, Macpherson T, Hikida T, Masu M
J Neurochem · 2026 Jan · PMID 41486756 · Full text
Sulf1 and Sulf2 are extracellular sulfatases that remove 6-O-sulfate from heparan sulfate and thereby regulate cell signaling. Previous studies have revealed that Sulf1/Sulf2 double knockout (KO) mice had defects in diff...
Sulf1 and Sulf2 are extracellular sulfatases that remove 6-O-sulfate from heparan sulfate and thereby regulate cell signaling. Previous studies have revealed that Sulf1/Sulf2 double knockout (KO) mice had defects in differentiation and axon guidance during development, but their functional roles in the adult brain remain largely unknown. We recently found that Sulf1 mRNA is highly expressed in the nucleus accumbens (NAc) shell and that Sulf1 expression is detected in both types of medium spiny neurons expressing dopamine D1 or D2 receptors. Moreover, we found that Sulf1 KO led to changes in membrane excitability and excitatory synaptic transmission in medium spiny neurons of the NAc in adult mice. These findings suggest possible roles of Sulf1 in the functions of NAc circuitry. To address this question, we performed behavioral tests using Sulf1 KO mice. We found that constitutive Sulf1 KO mice showed impairment in both the cocaine-induced conditioned place preference (CPP) test and inhibitory avoidance (IA) test. Next, to examine which cell types the Sulf1 gene is required for, we generated Sulf1 floxed mice by means of CRISPR-Cas9-mediated genome editing and mated them with mice expressing Cre recombinase under a promoter for either the dopamine D1 or D2 receptor-encoding genes. Sulf1 conditional knockout (cKO) in cells expressing dopamine D1 receptors led to impairment only in the CPP test, whereas Sulf1 cKO in D2 receptor-expressing cells resulted in impairment only in the IA test. These results demonstrate that Sulf1 is required for both reward and aversion learning, and that the D1- and D2-pathways distinctly regulate these functions. The present study suggests that Sulf1 is essential for neuronal functions and behavioral control in the adult brain.
The Enteric Nervous System as a Mediator of Microbiota-Gut-Brain Interactions in Parkinson's Disease.
Valdetaro L, Ricciardi MC, Almeida PP … +2 more , Stockler-Pinto MB, Tavares-Gomes AL
J Neurochem · 2026 Jan · PMID 41486750 · Full text
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which gastrointestinal dysfunction is highly prevalent and often precedes motor symptoms. Although research on gut microbiota alterations in PD h...
Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which gastrointestinal dysfunction is highly prevalent and often precedes motor symptoms. Although research on gut microbiota alterations in PD has expanded rapidly, inconsistent findings and the absence of a reproducible microbial signature reveal the limitations of a microbiota-centered view. The enteric nervous system (ENS), the intrinsic neural network of the gut, has been comparatively overlooked and remains underexplored, yet mounting evidence indicates that it undergoes profound alterations in PD. Pathological changes in enteric neurons and glial cells, including α-synuclein accumulation, disrupted neurotransmission, impaired epithelial barrier regulation, and neuroinflammation, not only contribute to gastrointestinal dysfunction but may also drive disease propagation along the gut-brain axis. In parallel, PD-related dysbiosis alters microbial metabolites and immune signaling, disrupting ENS physiology. This review reframes PD gut pathology by emphasizing the ENS as a central mediator of microbiota-brain communication. We highlight potential key pathways underlying this crosstalk, including short-chain fatty acids (SCFAs), Toll-like receptor (TLR) signaling, and serotonergic circuits, which normally sustain ENS function but, in the context of PD, contribute to barrier impairment, neuroinflammation, and neuronal alterations. By integrating evidence from human studies and experimental models, we argue that investigating ENS-microbiota interactions provides a more comprehensive perspective on PD pathophysiology and may guide the identification of novel biomarkers and therapeutic approaches capable of addressing both gastrointestinal and neurological manifestations of the disease.
Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives.
Fontes-Dantas FL, da Fontoura Galvão G, Cunha AM … +3 more , de Sena Murteira Pinheiro P, Morandi V, de Souza JM
J Neurochem · 2026 Jan · PMID 41486746 · Full text
Familial cerebral cavernous malformations (FCCM) are a heritable neurovascular disorder defined by clusters of dilated, thin-walled capillaries in the brain and spinal cord. Although rare, FCCM offers a tractable model f...
Familial cerebral cavernous malformations (FCCM) are a heritable neurovascular disorder defined by clusters of dilated, thin-walled capillaries in the brain and spinal cord. Although rare, FCCM offers a tractable model for understanding how genetic disruptions in endothelial junction biology, mechanotransduction, and kinase signaling drive vascular instability in the central nervous system. Pathogenic loss-of-function variants converge on signaling abnormalities that promote barrier dysfunction, iron deposition, inflammation, and progressive lesional growth. Clinically, FCCM may manifest with seizures, headaches, focal deficits, or intracerebral hemorrhage, yet many carriers remain asymptomatic owing to incomplete and age-dependent penetrance. Advances in neuroimaging have enhanced the detection of micro-lesions and iron accumulation, establishing these modalities as central biomarkers of disease expression. Complementing imaging, emerging circulating biomarkers, including inflammatory cytokines and plasma microRNAs associated with mutation status, may improve individualized risk stratification. This primer synthesizes current knowledge on FCCM pathophysiology, genetics, diagnostic strategies, and therapeutic perspectives. By integrating molecular mechanisms with clinical relevance, it outlines a framework for understanding FCCM as a disorder of perturbed endothelial signaling and neurovascular homeostasis, and highlights opportunities to advance precision medicine for this challenging condition.
Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers.
Valerio RR, Santos ÁR, Nóbrega AHL … +7 more , Martins R, De Felice FG, Ferreira ST, Savino W, Bonomo A, Bernardi A, Frozza RL
J Neurochem · 2026 Jan · PMID 41480929 · Full text
Microglia are the main innate immune cells residing in the brain parenchyma. Their activation and resulting neuroinflammation have emerged as major pathogenic mechanisms in neurodegenerative disorders, particularly in Al...
Microglia are the main innate immune cells residing in the brain parenchyma. Their activation and resulting neuroinflammation have emerged as major pathogenic mechanisms in neurodegenerative disorders, particularly in Alzheimer's disease (AD). The accumulation of amyloid-β oligomers (AβOs) and microglia activation play crucial roles in the pathogenesis of AD. In a second vein, the development of innate immune memory in response to different stimuli is a vital mechanism that enables microglia to adjust their response to subsequent inflammatory challenges. While there is increasing evidence that repeated bouts of peripheral inflammation lead to training or tolerance in microglia, the impact of tolerance on the inflammatory response induced by AβOs remains to be determined. In this study, we investigated whether lipopolysaccharide (LPS)-induced tolerance affects microglial responses to AβOs. For that, organotypic hippocampal cultures were repeatedly challenged with LPS before being exposed to AβOs. We measured cytokine levels and evaluated changes in microglial activation and morphology following exposure of cultures to AβOs. A significant decrease in cytokine production was observed when hippocampal slice cultures were repeatedly challenged with LPS. Interestingly, microglial activation and the resulting inflammatory response induced by AβOs were prevented when these cultures had been previously challenged with LPS. Moreover, the changes in microglial morphology and cytokine production resulting from repeated LPS stimulation were associated with reduced activation of nuclear factor kappa B (NF-κB). These results indicate that preconditioning microglia with LPS induces a physiological immune tolerance response rather than pathological inflammation, which may have implications for developing therapeutic strategies for AD aimed at modulating innate immune memory.
Memantine Confers Multi-Target Protection in a Zebrafish Seizure Model: Attenuating Epileptic Behavior, GluN2A Overexpression, and Oxidative Stress.
Zenki KC, Kalinine E, Mussulini BHM … +7 more , Dos Santos TG, von Mengden L, Klamt F, Baggio S, de Moura AC, da Veiga ABG, de Oliveira DL
J Neurochem · 2026 Jan · PMID 41480919 · Full text
Drug repurposing represents a strategic approach to identifying multi-target therapies for complex disorders like refractory epilepsy. Memantine (MN), a well-tolerated N-methyl-D-aspartate receptor (NMDAR) antagonist wit...
Drug repurposing represents a strategic approach to identifying multi-target therapies for complex disorders like refractory epilepsy. Memantine (MN), a well-tolerated N-methyl-D-aspartate receptor (NMDAR) antagonist with additional multi-target activities, is a promising candidate for repurposing. This study investigated the preventive effects of MN on pentylenetetrazol (PTZ)-induced seizures and its associated neurochemical and behavioral sequelae in adult zebrafish. Animals were pre-treated with MN (20 or 50 mg/kg, i.p.) or vehicle 1 or 2 h before PTZ exposure. Seizure behavior was assessed immediately, while neurochemical and behavioral analyses were conducted 24 h post-seizure. MN pre-treatment significantly attenuated seizure severity and delayed the onset of tonic-clonic seizures. Notably, MN prevented the PTZ-induced upregulation of the GluN2A NMDAR subunit and mitigated oxidative stress by reducing protein carbonylation and normalizing superoxide dismutase (SOD) activity. Furthermore, MN abolished the PTZ-induced increase in time spent in the white compartment of a light/dark test, a behavioral indicator of disrupted defensive responses. These results demonstrate that MN confers robust anticonvulsant, neuroprotective, and behavioral-stabilizing effects in a zebrafish seizure model. Our findings reinforce the potential of memantine as a novel multi-target adjunct therapy for mitigating the neurobehavioral consequences of epilepsy.
Writing the Engram: Epigenetic Mechanisms of Memory Allocation.
Tarulli I, Toscano-Rivalta R, Watt L … +1 more , Gräff J
J Neurochem · 2025 Dec · PMID 41470040 · Full text
Memory allocation, the selective recruitment of neurons into ensembles that encode, store and retrieve experience, so-called engram cells, designates the initial step of every memory's formation. Historically thought to...
Memory allocation, the selective recruitment of neurons into ensembles that encode, store and retrieve experience, so-called engram cells, designates the initial step of every memory's formation. Historically thought to be governed primarily by intrinsic neuronal excitability, recent studies highlight a critical role for transcriptional and epigenetic heterogeneity in biasing neuronal engram inclusion. Here, we review mechanisms that influence this process, including CREB-mediated excitability, transcriptional priming and epigenetic modulation, and emphasise the surprisingly understudied link of how electrical properties and the epigenetic landscape converge to shape allocation. We then describe emerging methodologies for the manipulation and interrogation of these processes that will be crucial for disentangling not only local intracellular dynamics, but also their propagation across distributed brain networks. Doing so will prove instrumental to assess the possibility that several cognitive dysfunctions-that display aberrant excitability and epigenetic changes-may arise from memory misallocation, stressing the translational potential of this work. Lastly, beyond the role of the intrinsic neuronal properties, we discuss underexplored physiological influences, including metabolic state, hormonal signalling, sleep, gut-brain communication, and the potential contribution from other cell types such as astrocytes and interneurons that may shape engram selection. By integrating molecular, cellular and systems perspectives, with a sharpened emphasis on the importance of epigenetic mechanisms, we suggest that understanding allocation may benefit from a holistic viewpoint beyond the current excitability-focused and neuron-centric point of view.
Cannabinoid Ligand-Mediated Glycogen Depletion in Astrocytes Is Associated With Increased Intracellular Calcium, Energy Metabolism, and Membrane Dynamics.
Fink K, Zorec R, Kreft M
J Neurochem · 2025 Dec · PMID 41457700 · Full text
Astrocytes orchestrate brain energy metabolism and respond to endocannabinoids via cannabinoid receptor type 1 (CB1R), whereas the contribution of CB2R remains uncertain. We combined live-cell Förster resonance energy tr...
Astrocytes orchestrate brain energy metabolism and respond to endocannabinoids via cannabinoid receptor type 1 (CB1R), whereas the contribution of CB2R remains uncertain. We combined live-cell Förster resonance energy transfer sensors for D-glucose and L-lactate, intracellular Ca imaging, glycogen assays, and whole-cell patch-clamp capacitance measurements to define how cannabinoid ligands shape astrocyte physiology in primary rat cultures. The CB1-selective agonist ACEA triggered rapid, transient elevations in [Ca]ᵢ and metabolic readouts, whereas the CB2-biased ligands AM1241 and Gp1a produced sustained metabolic effects, including prolonged increases in intracellular D-glucose and L-lactate. AM1241 additionally evoked glycogen depletion. Ligand applications also increased membrane capacitance, consistent with enhanced exocytotic activity and altered membrane dynamics. CB1 immunoreactivity predominated over a weak CB2-like signal, and RT-qPCR detected Cnr1 but not Cnr2 transcripts under our conditions. Accordingly, we interpret AM1241/Gp1a actions as ligand-evoked effects that are predominantly CB1-linked (and/or off-target at the concentrations used). Together, these results show that cannabinoid ligands robustly remodel astrocytic energy metabolism and membrane behavior chiefly through CB1-associated pathways, highlighting a functional axis between cannabinoid signaling, Ca mobilization, glycogen remodeling, and exocytosis in astrocytes.
Beta-Arrestin2-Biased Activation by Pilocarpine Suppresses Microglial Inflammatory Response.
Xie Y, Wang K, Wang S … +5 more , Yao Y, Wang D, Chen H, Zhao L, Xu J
J Neurochem · 2025 Dec · PMID 41457680 · Publisher ↗
Microglia play a pivotal role in inflammatory regulation through multifarious signaling pathways within the central nervous system, and mitigating microglial inflammation is considered a promising strategy to delay the p...
Microglia play a pivotal role in inflammatory regulation through multifarious signaling pathways within the central nervous system, and mitigating microglial inflammation is considered a promising strategy to delay the progression of neurodegeneration. However, the role of biased receptor signaling in modulating microglial inflammation remains largely unexplored. In this study, the anti-inflammatory effects and the underlying mechanism of muscarinic receptor agonists pilocarpine and iperoxo were explored. Our results showed that pilocarpine, rather than iperoxo, inhibited the expression of TNF-α and IL-6, as well as restored ramified morphology and physiological phagocytosis of over-activated microglia. RNA-seq revealed that pilocarpine-treated BV2 exhibited transcriptional profiles more similar to the control group, with upregulation of anti-inflammatory genes. β-arrestin2 knockdown attenuated the anti-inflammatory effect of pilocarpine by reversing the expression of inflammatory factors and activation of NF-κB. Furthermore, through chemogenetic DREADDs, activation of Gαq, Gαi, or β-arrestin pathways demonstrated that β-arrestin, but neither Gαq nor Gαi, inhibited the inflammatory response in microglia. Our findings proved that pilocarpine could abate the microglial inflammatory response via biased activation of the β-arrestin2 pathway, which could be considered a promising therapeutic approach for anti-neuroinflammation.
Post-Translational Modifications Distinguish Amyloid-β Isoforms in Cerebral Amyloid Angiopathy and Alzheimer's Disease.
Koutarapu S, Roberts KF, Coyle RA … +6 more , Mehla J, Sato C, Zipfel GJ, Bateman RJ, Schwetye KE, Mukherjee S
J Neurochem · 2025 Dec · PMID 41457650 · Full text
Cerebral amyloid angiopathy (CAA) shares amyloid-β (Aβ) deposition as a pathological hallmark with the extracellular plaques of Alzheimer's disease (AD). While both disease processes involve progressive, decades-long dep...
Cerebral amyloid angiopathy (CAA) shares amyloid-β (Aβ) deposition as a pathological hallmark with the extracellular plaques of Alzheimer's disease (AD). While both disease processes involve progressive, decades-long deposition of fibrillar Aβ peptide, they differ in isoform composition. We hypothesized that post-translational modifications (PTMs) on Aβ would also differ between CAA and parenchymal plaques. Using Lys-N enzymatic digestion followed by quantitative mass spectrometry, we profiled Aβ isoforms and N-terminus PTMs (aspartic acid isomerization and pyroglutamate formation) across CAA severity and compared them to parenchymal plaque Aβ in AD. Moderate to severe CAA were dominated by intact N-terminus (Aβ ~ 95%) with minimal N-truncated species (Aβ, Aβ, and Aβ), whereas parenchymal plaques displayed diverse N-terminus truncations and PTMs. Increasing CAA severity correlated with a shift from longer, hydrophobic C-terminal isoforms (Aβ, Aβ, and Aβ) to shorter, less hydrophobic C-terminal isoforms (Aβ, Aβ, Aβ, and Aβ). Importantly, moderate and severe CAA displayed minimal isomerization of Asp1 and Asp7 residues. These patterns suggest distinct Aβ aggregation mechanisms in CAA versus parenchymal plaques. We propose that the intact and unmodified N-terminus found in CAA is due to its inclusion within the protofibril structure making them less disordered and inaccessible to post-translational modifications, in contrast to plaque-associated Aβ. These biochemical differences may reflect underlying structural distinctions in protofibril architectures, with potential implications for biomarker development for early CAA detection and therapeutic targeting of vascular versus parenchymal Aβ.
Maternal Obesity in Pregnancy: Risk Factor for Neurodevelopmental Outcomes in Offspring.
Schmitt LO, Faraco G, Stivanin TS … +1 more , Gaspar JM
J Neurochem · 2025 Dec · PMID 41452351 · Full text
Obesity is a worldwide epidemic disease marked by changes in the function of various tissue and organs, driven by excessive fat accumulation. In recent years obesity was characterized not just by the increase of fat, but...
Obesity is a worldwide epidemic disease marked by changes in the function of various tissue and organs, driven by excessive fat accumulation. In recent years obesity was characterized not just by the increase of fat, but also an imbalance of energy homeostasis mechanisms. In parallel with global rise in obesity, the incidence of obesity during pregnancy and lactation had also been steadily increasing. Maternal obesity is a public health issue that affects the child and the mother, in acute and chronic term, being a risk factor for the development of metabolic, hormonal, neurodevelopmental, and psychiatric disorders in offspring. Obesity during the gestation can reprogram the fetal immune, metabolic, endocrine, and neurological systems, influencing offspring's metabolism and mental health. This is supported by the Developmental Origins of Health and Disease (DOHaD) theory, which proposes that environmental factors during critical periods of early development (as the fetal period) can influence the risk of developing diseases later in life. In this review, we focused on how maternal obesity can affect the brain offspring neurodevelopment, neural circuits, synapses, glial cells, and neuroinflammation, which all can influence offspring behavioral disorders.
A Mutation in Vesicular Acetylcholine Transporter Increases Tubulin Acetylation Compromising Synaptic Vesicle Transport.
Kuo CS, Ruckmani VM, Wang MC … +5 more , Khawaja MS, Bayansan O, Barmaver SN, Bhan P, Wagner OI
J Neurochem · 2025 Dec · PMID 41452330 · Publisher ↗
Kinesin-3 UNC-104(KIF1A) is the major anterograde axonal transporter of synaptic vesicles and is expressed pan-neuronally. Genetic defects in this molecular motor are linked to KIF1A-associated neurological disorders (KA...
Kinesin-3 UNC-104(KIF1A) is the major anterograde axonal transporter of synaptic vesicles and is expressed pan-neuronally. Genetic defects in this molecular motor are linked to KIF1A-associated neurological disorders (KAND), a spectrum of severe neurological conditions encompassing Charcot-Marie-Tooth (CMT) disease and hereditary spastic paraplegia (HSP). From a candidate screen for genes causing neurotransmission defects in C. elegans and simultaneously affecting post-translational modification of tubulin, we identified allele unc-17(e245) significantly elevating tubulin acetylation in vitro and in vivo. UNC-17 encodes for a VAChT (vesicular acetylcholine transporter) and its human ortholog SLC18A3 is implicated in Alzheimer's and Huntington's disease. To exclude secondary effects of the unc-17 mutation, we tracked UNC-104 and RAB-3 motility in the non-cholinergic ALM neuron. With upregulated tubulin acetylation in ALM (anterior lateral microtubule) neurons in unc-17(e245) strains (visualized by immunostaining), motility of both motor and its cargo is significantly compromised. However, motility of UNC-104 improves when knocking down α-tubulin acetyltransferase MEC-17(ATAT1) in unc-17(e245) strains and, conversely, is negatively affected when overexpressing MEC-17 in wild type animals. Similar effects were observed in cholinergic sublaterals. UNC-17 and UNC-104 colocalize in cholinergic head neurons, consistent with a motor-cargo relationship. Strikingly, mec-17 knockdown significantly decreases their colocalization, while unc-17 knockdown reduces UNC-104/MEC-17 colocalization in head neurons. Direct protein-protein interactions were validated through bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation (Co-IP) assays. In both assays, mec-17 knockdown significantly reduced the UNC-104/UNC-17 associations, whereas unc-17 knockdown significantly diminished UNC-104/MEC-17 interactions. These findings indicate a tripartite regulatory complex UNC-104/UNC-17/MEC-17. We propose that unc-17 knockdown disrupts sequestration of MEC-17 within this complex and that the release of MEC-17 results in increased tubulin acetylation. Resulting elevated tubulin acetylation suppresses UNC-104 motor processivity and cargo transport efficiency.
Neuroprotective Effects of PEP-1-PGAM5 via the Attenuation of Oxidative Stress and Apoptosis in Parkinson's Disease.
Kwon HJ, Jung HY, Yoo DY … +2 more , Moon SM, Kim DW
J Neurochem · 2025 Dec · PMID 41452269 · Publisher ↗
Parkinson's disease (PD) is driven by mitochondrial impairment and oxidative stress-induced dopaminergic cell death. Phosphoglycerate mutase 5 (PGAM5) augmented accelerating mitophagy and attenuating neuronal apoptosis....
Parkinson's disease (PD) is driven by mitochondrial impairment and oxidative stress-induced dopaminergic cell death. Phosphoglycerate mutase 5 (PGAM5) augmented accelerating mitophagy and attenuating neuronal apoptosis. Here, we present a novel cell-penetrating PEP-1-PGAM5 fusion protein designed to suppress oxidative damage and apoptosis. We assessed its transduction efficiency and neuroprotective efficacy in vitro and in vivo. PEP-1-PGAM5 was efficiently transduced into SH-SY5Y cells without cytotoxicity. In MPP-exposed cells, PEP-1-PGAM5 attenuated ROS generation, prevented DNA fragmentation, and restored apoptotic signaling. In PD animal model, PEP-1-PGAM5 crossed the blood-brain barrier, preserved tyrosine hydroxylase-positive neurons, and modulated apoptosis markers. These findings demonstrate that delivery of mitochondrial phosphatase PGAM5 via PEP-1 not only mitigates key PD pathologies but also establishes a versatile platform for delivering therapeutic proteins to the brain. PEP-1-PGAM5 thus represents a promising candidate for PD and other neurodegenerative disorders.
Convergent Recruitment of Cerebellar Purkinje Cells by Mechanistically Diverse General Anesthetics.
Utsumi N, Tanaka DH, Nakai A … +4 more , Inaba S, Nonaka S, Maeda S, Uesaka N
J Neurochem · 2025 Dec · PMID 41452264 · Full text
General anesthesia produces a rapid and reversible loss of consciousness, yet the neural circuits through which chemically unrelated agents achieve this state remain largely unknown. Here, we combined Targeted Recombinat...
General anesthesia produces a rapid and reversible loss of consciousness, yet the neural circuits through which chemically unrelated agents achieve this state remain largely unknown. Here, we combined Targeted Recombination in Active Populations (TRAP), Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC) tissue clearing, and light-sheet microscopy to generate a hemisphere-wide, single-cell atlas of neurons activated by three mechanistically distinct anesthetics in adult Fos; R26 (TRAP2; Ai14) female mice. Automated alignment to the Atlas and unbiased effect-size analysis across 252 regions revealed a striking convergence. Vermal cerebellar lobules and their deep nuclei ranked at the top for every drug, whereas neocortical and thalamic areas showed mixed or drug-specific patterns. Within the cerebellum, the major population of tdTomato-labeled cells was the Purkinje cells, as confirmed by manual counting. Two additional subcortical hubs, the lateral paragigantocellular nucleus and external globus pallidus, were activated by all three agents, suggesting a broader cerebello-autonomic network. These results position Purkinje cells as a commonly activated population by chemically divergent anesthetics, raising the possibility that general anesthesia produces a state of loss of consciousness through the activation of Purkinje cells.
The Lipidome of the Lateral Ventricle Choroid Plexus Exhibits Sex-Specific Changes Across Aging.
Loupiac G, Andriambelo B, Avila-Lopez J … +9 more , Vachon A, Avino M, Ahumada JR, Miard S, Picard F, Qiu Y, Kurland IJ, Laurent B, Plourde M
J Neurochem · 2025 Dec · PMID 41432428 · Full text
During aging, the brain's lipid composition and the cerebrospinal fluid (CSF) secreted by the choroid plexus (ChP) undergo significant modifications. The ChP, an epithelial tissue located in each brain ventricle, experie...
During aging, the brain's lipid composition and the cerebrospinal fluid (CSF) secreted by the choroid plexus (ChP) undergo significant modifications. The ChP, an epithelial tissue located in each brain ventricle, experiences a decline in key functions, including protein secretion and CSF production. A critical gap in our understanding of the ChP lies in its lipid composition and the potential impact of age-related changes on its physiology. This study hypothesized that the lipidome of the lateral ventricle choroid plexus (LVCP) is modulated during aging, potentially generating pro-inflammatory mediators. To address this, we performed quantitative lipidomics on LVCP from male and female mice across aging and investigated whether pro-inflammatory lipid mediators increase with age. LVCP and cortex tissues from C57BL/6 mice aged 6, 12, 18, and 24 months (n = 5/age/sex) were analyzed using liquid chromatography-tandem mass spectrometry, and data were processed using Lipidr and univariate statistical methods. Given the pronounced sex differences, analyses were stratified by sex. During aging, 9 lipids in males and 19 in females were significantly modulated. In males, most changes occurred at 24 months and involved higher levels of arachidonic acid (ARA) in alkyl ether and plasmalogen phosphatidylcholine species. In females, most changes occurred at 18 months and were characterized by lower levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whereas at 24 months, females exhibited higher levels of EPA, DHA, and ARA in alkyl ether and plasmalogens compared to other ages. Additionally, younger females showed higher levels of oxygenated derivatives of linoleic acid compared to older females. These findings reveal dynamic, sex-specific remodeling of the LVCP lipidome during aging, suggesting that lipid homeostasis in this structure is tightly regulated and may influence inflammatory signaling and barrier function in an age-dependent manner.
Postnatal Mouse Brain Region-Resolved Peptidomic Resource of Conditional Ndel1 Loss: Comparison of Acidic and Alcoholic Extraction Strategies.
Nani JV, Hayashi JY, Campeiro JD … +7 more , Câmara GA, Saito A, Oyadomari WY, Sawa A, Kamiya A, Tashima AK, Hayashi MAF
J Neurochem · 2025 Dec · PMID 41432414 · Full text
The oligopeptidase Ndel1 (NudE neurodevelopment protein 1 like 1) is a multifunctional protein implicated in neurodevelopmental processes, intensively investigated as a potential biomarker in psychiatric disorders. While...
The oligopeptidase Ndel1 (NudE neurodevelopment protein 1 like 1) is a multifunctional protein implicated in neurodevelopmental processes, intensively investigated as a potential biomarker in psychiatric disorders. While its roles in regulating the cytoskeleton are well-studied, the global consequences of its loss on the brain's peptide landscape are unknown. This study presents a comprehensive, region-resolved peptidomic resource detailing the consequences of postnatal Ndel1 loss in the mouse cortex, hippocampus, striatum, and cerebellum. We also validated this method of microwave protease inactivation followed by acidic and organic extractions by means of this peptidome analysis across several brain regions. More specifically, using a conditional knockout mouse model with Ndel1 deletion in forebrain excitatory neurons, we employed complementary acidic and alcoholic extraction workflows coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS). We generated a comparative atlas of differentially abundant peptides (DAPs), identifying hundreds of peptide changes across the different brain regions and extraction methods. Gene Ontology analysis of the inferred source proteins revealed alterations in pathways related to cytoskeletal organization, synaptic function, and cellular metabolism. This dataset provides a foundational resource for generating new hypotheses about Ndel1's region-specific functions and serves as a valuable reference for the neurodevelopmental and neuropeptidomics communities. Understanding these Ndel1-driven changes is crucial, providing valuable insights into the pathophysiology of neurodevelopmental and mental disorders linked to reduced Ndel1 activity, such as schizophrenia, autism, and bipolar disorder. This holistic view may reveal novel therapeutic targets for these complex conditions.
Oral KDS2010, a Monoamine Oxidase-B (MAO-B) Inhibitor, Slows the Deterioration of Motor Coordination in Genetic SCA1 Models by Inhibiting Astrocytic MAO-B-Mediated Inflammation.
Woo DH, Jeon JH, Ryu HJ … +5 more , Lee GM, Lim HW, Park KD, Hoe KL, Rhee SD
J Neurochem · 2025 Dec · PMID 41427729 · Full text
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by balance and gait disturbance, muscle coordination deficits, and dysarthria as a primary symptom. SCA1 is caused by...
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by balance and gait disturbance, muscle coordination deficits, and dysarthria as a primary symptom. SCA1 is caused by the expansion of CAG repeats in the ATXN1 gene, leading to a polyglutamine(polyQ) tract in the Ataxin-1 protein. In this study, the effects of KDS2010, an inhibitor of monoamine oxidase-B (MAO-B), were evaluated in a transgenic mouse model of SCA1 (SCA1) disease model using the rotarod, hindlimb, and open field tests. In both males and females, oral administration of KDS2010 significantly improved latency in the rotarod test and the hindlimb clasping phenotype without changing muscle weight. In the open field test, a notable improvement in moving distance was observed particularly in females. Treatment with KDS2010 slowed molecular layer atrophy and restored the reduced number of Purkinje cells in the cerebellum of SCA1 model mice, accompanied by decreased levels of glial fibrillary acidic protein (GFAP) and reduced expression of monoamine oxidase-B (MAO-B). These results indicate that KDS2010 ameliorated the behavioral pathology of SCA1 by attenuating GFAP upregulation and preventing Purkinje cell loss. Our findings demonstrate that KDS2010 improves SCA1-related behavioral deficits by reducing GFAP expression, preserving Purkinje cell numbers, and decreasing cerebellar MAO-B levels-molecular markers of SCA1, without affecting muscle size.
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