Journal of Neurochemistry最新文献

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.

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.

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.

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.

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.

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.

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_1-x ~ 95%) with minimal N-truncated species (Aβ_2-x, Aβ_3pGlu-x, and Aβ_4-x), whereas parenchymal plaques displayed diverse N-terminus truncations and PTMs. Increasing CAA severity correlated with a shift from longer, hydrophobic C-terminal isoforms (Aβ₄₁, Aβ₄₂, and Aβ₄₃) to shorter, less hydrophobic C-terminal isoforms (Aβ₃₇, Aβ₃₈, Aβ₃₉, and Aβ₄₀). 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.

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 Ca²⁺ 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 [Ca²⁺]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, Ca²⁺ mobilization, glycogen remodeling, and exocytosis in astrocytes.