Journal of Neurochemistry最新文献

The prefrontal cortex (PFC) is critical for regulating stress responses through top-down control over limbic and subcortical structures. The PFC undergoes a prolonged developmental process that only reaches maturation during adulthood, causing it to be highly sensitive to environmental insults during neurodevelopment, such as adolescence. During this critical period, synaptic pruning, the maturation of inhibitory GABAergic interneurons, and the refinement of dopaminergic transmission collectively establish the excitatory-inhibitory balance necessary for adaptive behavior. Impairment of the PFC due to developmental disruptions increases susceptibility to maladaptive stress responses. These responses can, in turn, contribute to the development of major depressive disorder and schizophrenia. In depression, a dysfunctional PFC fails to effectively inhibit the amygdala, which contributes to hyperactivity in stress-related circuits, hypodopaminergic states, and anhedonia. In schizophrenia, a neurodevelopmental PFC dysfunction would precipitate hippocampal circuit disruption driven by stress. The inability of an immature PFC to regulate the amygdala response to stress would trigger an increased excitatory drive to the ventral hippocampus, which is proposed to underlie the excessive limbic drive, hippocampal hyperactivity, and a hyperdopaminergic state. In addition, the activation of the mesocortical dopaminergic system by stress facilitates the PFC response to stress, both during adulthood and adolescence. A dopamine (DA)-induced unregulated stress response disrupts the excitatory and inhibitory transmission within the PFC, which plays a critical role in its function. Understanding the interplay between stress and PFC activity/maturation to regulate the circuit toward adaptive or maladaptive outcomes offers critical insights for early intervention and prevention. Early changes in the PFC could underlie vulnerability to unregulated stress response and its consequent effect in contributing to schizophrenia and depression. In this way, early intervention may limit the impact and prevent further circuit dysregulation leading to pathological states.

The core mechanisms underlying aging involve genomic instability, cellular senescence, mitochondrial dysfunction, and chronic inflammation, necessitating multi-dimensional therapeutic interventions. Treg-derived extracellular vesicles (Treg-EVs) therapy, which circumvents the safety risks associated with live cell therapies, exhibits the potential to modulate metabolic and immune functions, offering promise for healthy aging. Here, we isolated Tregs from young male C57BL/6 mice and collected Treg-EVs. In vitro experiments demonstrated that Treg-EVs significantly attenuated cellular senescence, reduced reactive oxygen species (ROS) accumulation, and enhanced mitochondrial respiration in HL-1 and HT22 senescent cell models. In vivo experimental data revealed that young Treg-EVs promoted mitochondrial biogenesis, facilitated vascular repair and regeneration, as well as attenuated inflammatory responses, and ultimately prolonged the survival of aged male C57BL/6 mice. This study demonstrates the ability of Treg-EVs therapy to reverse multiple aging-related abnormal phenotypes, providing a promising strategy for treating aging and its associated diseases.

Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.

Glucocorticoids (GCs) are central to the organism's adaptation to stress, coordinating systemic energy distribution and neuroendocrine signaling. While acute effects of GCs are adaptive, chronic GC exposure is increasingly recognized as an important factor contributing to the pathophysiology of neuropsychiatric disorders, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). A piling evidence points to astrocytes as a central integrator of brain response to stress hormones, including GCs. In this review, we discuss a biphasic regulation of astrocyte metabolism by GCs. According to the hypothesis, astrocytes undergo metabolic adaptations in response to GC: acute exposure leads to the enhancement of astrocyte metabolism through upregulation of glycolysis, mitochondrial activation, and glutamate clearance. In turn, prolonged GC exposure induces a metabolic shift toward branched-chain amino acid and lipid catabolism, promoting mitochondrial reactive oxygen species (ROS) production and impairing key homeostatic functions, including the astrocyte-neuron lactate shuttle and calcium signaling. Progressive disruption of astrocytes' supporting function may subsequently lead to synaptic dysregulation and energy imbalance in stress-related brain pathology. We postulate that a detailed understanding of this dynamic regulation is necessary for targeting astrocyte-specific metabolic mechanisms in neuropsychiatric disorders.

Gestational transfer of brain-reactive antibodies is a risk factor for neurodevelopmental disorders. Contactin-associated protein-like 2 (CASPR2) is a known target for pathogenic maternal autoantibodies which have been proposed to interfere with fetal neurodevelopment. However, the impact of CASPR2 antibodies on human brain development remains largely unknown. Here, to better understand the neurophysiological changes that occur in the presence of these pathogenic autoantibodies, we cultured unguided human neural organoids for a period of 6-months in media containing anti-CASPR2 antibodies. We then performed neurophysiological characterization via whole-cell patch-clamp and calcium imaging in acute organoid slices. Our results reveal that CASPR2 antibody exposure increased spontaneous synaptic activity, enhanced the maximal frequency of action potential firing and of spontaneous network activity. These findings are consistent with a state of neuronal hyperexcitability, a phenotype which is observed in several models of neurodevelopmental disorders. Mechanistically, the alterations observed in action potential waveform are in accordance with a role for CASPR2 in the regulation of voltage-gated potassium channels and a pathological role for CASPR2 autoantibodies in driving neuronal hyperexcitability.

Schwann cells communicate with neurons not only through soluble cues but also via intercellular transfer of ribosomes and exosome-mediated delivery of cargo. Recent studies have established that Schwann cell-derived exosomes are powerful promoters of nerve repair, capable of enhancing axon regrowth, remyelination, and functional recovery in numerous models. These effects are mediated via multifactorial cargo (miRNAs, mRNAs, proteins) that modulate neurons, glia, endothelial, and immune cells. Importantly, what began as a novel biological insight is now rapidly moving toward therapeutic innovation. Schwann cell-derived exosomes thus represent both a novel mode of glia–neuron communication and a promising avenue for next-generation therapies for nerve regeneration.

Sulfonamide-based compounds have been a clinically attractive scaffold for drug development and proven as antioxidant and antimicrobial agents, but their pharmacological derivatives containing anthranilates (SA1–4) and therapeutic targets are not clearly clarified. To unravel the neuroprotective roles and underlying mechanisms of SA1–4 against oxidative injury and healthy longevity crosstalk, a combination of in vitro experiments, in silico modeling, and network pharmacology was employed. Pretreatment with SA1–4 in human neuronal SH-SY5Y cells significantly regulated sirtuins (SIRTs)/forkhead box class O 3a (FOXO3a)-mediated longevity signaling pathway via targeting endogenous antioxidant enzymes (i.e., superoxide dismutase 2 [SOD2] and catalase [CAT]), apoptotic cascades (i.e., Bcl-2-associated X-protein [BAX] and B-cell lymphoma-2 [BCL-2]), mitochondrial balance, and ultimately led to the neuronal rescue. Molecular docking simulations support the possibility of the SA1–4 modulatory effect within the active binding site of SIRT1. Importantly, in silico predictions of pharmacokinetic profiles suggested that the synthetic compounds possessed preferable drug-like properties, good oral bioavailability, and safety profiles. Network pharmacology also revealed the involvement of SA1–4 and key targets-regulated SIRTs in neurodegeneration, including non-amyloidogenic cascade, tau phosphorylation, calcium homeostasis, insulin-mediated glucose uptake, and neuroinflammation. Therefore, SA1–4 exert promising multi-target therapeutic strategies against oxidative damage, potentially offering alternative anti-Alzheimer candidates for further clinical neurodegenerative and anti-aging therapeutics.

Emotional well-being is a multifactorial concept, which comprises not only life quality of human individuals, but also their mental and physical health. It encompasses several key parameters, many of which have behavioral representation in daily life. These include finding positive meaning of life events, ability to maintain supportive and caring social interactions, reward-oriented behavior, and many others. It is well-known that the behavioral phenotype is tightly bound to certain physiological and metabolic factors, among which sphingolipid (SL) balance of the organism and especially central nervous system might play an important role. Recent research proposes that SLs mediate multiple components of emotional well-being. The most abundant brain SL types, ceramides and gangliosides, dynamically shape the composition of protein carrying cellular membranes and overall neuronal plasticity. Multiple studies show the contribution of SLs to normal brain functioning and corresponding beneficial behavioral phenotypes, such as stress resilience, cognitive performance, and social interactions, which determine emotional well-being. On the other hand, an imbalance in SL metabolism affects normal functioning of cells and thus contributes to the development of several psychiatric disorders, such as depression, anxiety, cognitive decline, schizophrenia, and others. SLs are suggested as a potentially new mechanism of the key behavioral manifestations of emotional well-being, which might be further investigated as new biomarkers of life quality as well as physical and mental resilience.