Journal of integrative neuroscience最新文献

Background: Mitochondrial dysfunction is closely associated with the pathogenesis of Parkinson's disease (PD). Lutein has been shown to exert protective effects in neurological disorders. This study aimed to investigate the ameliorative effects of lutein on mitochondrial function in PD and its underlying molecular mechanisms.

Methods: Animal and cellular PD models were established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and treatment of SH-SY5Y cells with 1-methyl-4-phenylpyridinium ion (MPP⁺), respectively. Motor function was assessed using the rotarod, adhesive removal, and pole tests. Mitochondrial function was evaluated using MitoSOX Red staining, JC-1 staining, and adenosine triphosphate (ATP) content measurement. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to measure the levels of relevant proteins and mRNA.

Results: Lutein significantly ameliorated MPTP-induced motor dysfunction in PD mice, increased the number of tyrosine hydroxylase (TH)-positive neurons, and alleviated damage to striatal brain tissue. At the cellular level, lutein significantly suppressed MPP⁺-induced apoptosis of SH-SY5Y cells, upregulated the expression of B-cell lymphoma-2 (Bcl-2), and downregulated the expression of Bcl-2-associated X protein (Bax) and cleaved caspase-3. Additionally, lutein significantly reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential, increased ATP levels, and increased the activity of mitochondrial respiratory chain complex I. At the molecular level, lutein promoted the ubiquitination of dynamin-related protein 1 (Drp1), whose degradation was impaired in the PD model. This effect was mediated by the E3 ubiquitin ligase Tripartite Motif-containing protein 31 (TRIM31), whose expression was downregulated in the disease state. Functional experiments confirmed that overexpression of TRIM31 enhanced Drp1 ubiquitination and improved mitochondrial function, whereas TRIM31 knockdown partially attenuated the therapeutic effects of lutein.

Conclusion: In summary, this study revealed, for the first time, that lutein alleviates PD progression by increasing Drp1 ubiquitination and degradation via TRIM31 transcription and translation, ultimately improving neuronal mitochondrial function. These findings not only elucidate a novel mechanism underlying lutein's neuroprotective effect but also identify a potential therapeutic target and offer a new strategy for PD treatment.

Background: Recent studies have indicated that stem cells could provide therapeutic benefits in several neurological conditions, including Alzheimer's disease (AD). Adipose-derived stem cells (ADSCs) offer many advantages in that they are readily available from individual hosts, are robust, and secrete many factors that promote neuronal growth and homeostasis.

Methods: We transfected ADSCs with a viral construct for brain-derived neurotrophic factor (BDNF) and examined the effects of transplanting these cells into the hippocampus of 7-mo-old APPswe/PS1dE9 mice. After 6 mo, the hippocampus was examined for stem-cell survival, effects on BDNF and neprilysin-2 (NEP-2) levels, dendritic morphology using microtubule associated protein 2 (MAP2) immunohistochemistry, and amyloid plaque load.

Results: We found that transplanted BDNF-ADSCs had survived after 6 mo. BDNF and NEP-2 levels were higher than sham controls, and dendritic architecture was improved. In addition, amyloid plaque numbers were reduced.

Conclusions: BDNF-ADSCs appear to confer benefits by simultaneously enhancing amyloid clearance and promoting neuronal structural repair. This multifaceted approach highlights the potential of engineering stem cells to target multiple pathophysiological hallmarks of AD, positioning BDNF-ADSCs as a powerful and synergistic cell-gene therapy strategy for this devastating disorder.

Background: The perineuronal net (PNN) is an important extracellular environment around parvalbumin interneuron (PV IN) in the spinal cord. Chondroitin sulfate proteoglycan (CSPG) serves as a key factor mediating PNN effects on the spinal cord, primarily formed by covalently linked chondroitin sulfate glycosaminoglycan (CS-GAG) chains and diverse core proteins. Extensive research suggests that degradation of CS-GAG following nerve injury may contribute to severe spinal cord damage. Inhibiting CS-GAG degradation could enhance PNN stability and plasticity, thereby promoting recovery from nerve injury. Electroacupuncture (EA) intervention demonstrates significant neuroprotective effects, facilitating restoration of spinal cord nerve function and axonal regeneration. This study aims to observe the changes in CS-GAG and the expression of PV IN after spinal cord injury (SCI) in rats and explore the effect.

Methods: An SCI model was established in Sprague-Dawley rats using an Infinite Horizon (IH) impactor, and EA was applied to the Jia-ji acupoints (EX-B2). The Basso-Beattie-Bresnahan (BBB) score of SCI rats was evaluated, and electromyography (EMG) of the gastrocnemius muscle of the hind limbs was performed. The protein expression levels of CS-GAG and glutamic acid decarboxylase (GAD) were detected using western blotting, and perineuronal nets (PNN) and PV IN were observed using immunofluorescence (IF). Fiber-optic calcium imaging was used to detect and analyze PV IN activity. Adeno-associated virus containing carbohydrate sulfotransferase 11 (Chst11) was injected into T9 and T10 spinal cord spaces using a microneedle, and changes in CS-GAG in the spinal cord of SCI rats before and after EA intervention were observed.

Results: CS-GAG and GAD expression levels were significantly decreased after SCI and PNN stability was reduced. Chondroitinase ABC (ChABC) treatment increased PV IN activity and GAD expression. EA effectively promoted an increase in CS-GAG and GAD, improved PNN stability and PV IN activity, and reversed the inhibitory effect of Chst11, thereby facilitating the rehabilitation of rats with SCI.

Conclusion: The mechanisms and effects of EA on SCI repair were investigated. The results revealed that EA can regulate the recovery of PNN structure and function via CS-GAG and GAD, improve PV IN activity, and reverse the inhibitory effect of Chst11 to promote SCI rehabilitation in rats.

Background: The protective Icelandic mutation in the amyloid precursor protein (APP) gene, APP^A673T, identified in Icelandic and other Nordic populations is associated with a significantly lower risk of developing Alzheimer's disease (AD). Conflicting results have been reported for the human APP^A673T mutation in various knock-in models of AD, but the effect of the mouse APP^A673T form in 5× familial AD (5×FAD) mice has never been investigated.

Methods: We crossed C57Bl6/J mice expressing a single point mutation edited into the murine APP gene via Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated (CRISPR-Cas) gene editing, termed mAPP^A673T, with 5×FAD mice that overexpress human APP carrying the Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations as well as human presenilin-1 (PS1) with two mutations (M146L and L286V); the resulting mice were termed 5×FAD × mAPP^A673T mice. We investigated amyloid beta-protein (Aβ) pathology in 5×FAD × mAPP^A673T, 5×FAD and their respective controls, mAPP^A673T, and C57Bl6/J wild type mice, at 6-months of age using immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay (ELISA).

Results: We found a moderate yet significant reduction in Aβ plaque size in male 5×FAD × mAPP^A673T compared with 5×FAD mice. No differences were observed for soluble/insoluble Aβ40 and Aβ42 levels per se, but lower plaque count/area was found in 5×FAD × mAPP^A673T mice when Aβ42/Aβ40 ratios were low, suggesting a genotype-dependent sensitivity to Aβ aggregation and accumulation.

Conclusions: The mAPP^A673T mutation has the potential to modify Aβ pathology in 5×FAD mice at the age of 6 months.

Background: Executive dysfunction is the most prominent feature of cognitive impairment in patients with end-stage renal disease (ESRD). The dorsolateral prefrontal cortex (DLPFC) is a central region for the regulation of executive functions. The aim of our study was to examine alterations in neural activity and functional connectivity (FC) of the DLPFC in relation to cognitive assessments and clinical indicators in patients with ESRD using the resting-state functional magnetic resonance imaging (rs-fMRI) technique, and to further predict cognitive-related brain damage in this population.

Methods: A total of 37 ESRD patients and 35 normal controls received MRI scans and neuropsychological assessments. Inter-group differences in fractional amplitude of low-frequency fluctuations (fALFF) and FC of the DLPFC were compared. Additionally, the relationships between DLPFC abnormalities and cognitive function were analyzed in ESRD patients, along with the clinical characteristics. Finally, we ascertained the potential of DLPFC abnormalities to predict cognitive-related brain damage using receiver operating characteristic (ROC) curve analysis.

Results: ESRD patients exhibited decreased fALFF in the bilateral DLPFC (p < 0.05, false discovery rate [FDR] corrected). These also showed abnormal FC with the frontoparietal cortex, cingulate cortex, cerebellar posterior lobe, inferior temporal gyrus, and rolandic operculum (p < 0.05, FDR corrected). Several alterations in the DLPFC were associated with cognitive assessments (p < 0.05) in ESRD patients, and were also correlated with the levels of uric acid and hemoglobin (p < 0.05). Importantly, ROC curve analysis showed the fALFF value of left DLPFC, and FC between right DLPFC and right middle frontal gyrus effectively predicted cognitive-related brain damage in patients with ESRD.

Conclusions: This study demonstrated that the DLPFC is an important pathological brain region associated with the cognitive impairment of ESRD patients. Our results provide neuroimaging insights to further understand neural mechanisms of cognitive decline in this population.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and impaired insulin sensitivity. Although classified as a metabolic disorder, T2DM also contributes to cognitive decline. Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. T2DM is strongly associated with AD and is considered a major risk factor for its development. AD is therefore recognized as a metabolic disorder mediated by cerebral insulin resistance, often termed "type 3 diabetes". T2DM and AD exhibit crosstalk, sharing overlapping molecular mechanisms including insulin resistance, mitochondrial dysfunction, oxidative stress, chronic inflammation, autophagy dysregulation, tau hyperphosphorylation, and β-amyloid deposition. Among these, insulin resistance may play a potential role in this interplay. As a non-pharmacological intervention, exercise demonstrates distinct advantages in preventing and managing metabolic and neurological disorders. Exercise maintains glucose homeostasis by mitigating insulin resistance, enhances insulin sensitivity, and concurrently reduces tau hyperphosphorylation and β-amyloid aggregation, thereby improving cognitive function. Building on current literature, this review explores how exercise mitigates insulin resistance to prevent and manage both T2DM and AD. It further proposes that insulin resistance may serve as a potential mechanistic link through which exercise modulates the pathological crosstalk between the two disorders.

Background: Epilepsy is a complex neurological disorder marked by recurrent, unprovoked seizures. Ferroptosis is characterized by the accumulation of oxidative stress and is associated with the occurrence and development of epilepsy. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has demonstrated neuroprotective properties in various neurodegenerative conditions. In this study, we examined the antiepileptic efficacy of TUDCA and sought to elucidate its underlying mechanisms of action.

Methods: The antiepileptic effects of TUDCA were evaluated using electroencephalogram recordings, behavioral testing, and immunohistochemistry in a Lithium chloride (LiCl)- Pilocarpine (Pilo)-induced epilepsy rat model, alongside a glutamate-induced neuronal cell model. Neuronal ferroptosis was assessed through western blotting and immunofluorescence.

Results: In vivo, TUDCA significantly alleviated both seizure severity and neuronal damage by inhibiting oxidative stress and ferroptosis. In vitro, TUDCA similarly exerted neuroprotective effects and effectively suppressed neuronal ferroptosis.

Conclusion: TUDCA mitigates epilepsy through the suppression of ferroptosis, suggesting its potential as a therapeutic agent for epilepsy treatment.

The pathological increase in brain catabolites after traumatic brain injury strongly correlates with a higher risk of neurodegenerative disease. This review examines the pathogenic role of glymphatic clearance dysfunction in that process. The glymphatic network enables cerebrospinal and interstitial fluid exchange and paracellular flow. These processes are mediated by astrocytic aquaporin-4. Glymphatic function is regulated by arterial pulsatility, sleep-wake cycles, and intramural periarterial drainage, with meningeal lymphatic vessels acting as the final drainage site. Mechanical trauma causes aquaporin-4 depolarization and mislocalization; it also triggers neuroinflammatory activation and blood-brain barrier disruption. These processes ultimately impair glymphatic function and neurotoxic proteins become more localized and overproduced. Previous studies have linked clearance defects to secondary neuron injury. Current evidence in humans has come mostly from pilot studies. Recent advances in neuroimaging provide new assessment tools. Dynamic contrast-enhanced magnetic resonance imaging (MRI) reveals delayed tracer clearance. Diffusion tensor imaging along perivascular spaces shows abnormalities in key parameters. These imaging findings preliminarily associate with fluctuations in cerebrospinal fluid catabolites. Therapeutic research suggests several reparative strategies. Physical exercise improves aquaporin-4 polarization integrity. Cannabidiol administration in experimental models increases meningeal lymphatic drainage and reduces tau pathology. Angiotensin II type 1 receptor antagonists may indirectly improve clearance by stabilizing the blood-brain barrier. Lymphatic pathways have been used as therapeutic targets for cannabidiol. Biological evidence also supports their role in traumatic brain injury progression. Further investigation is needed to validate whether these represent independent contributing processes. Multimodal imaging, novel biomarker assays, and chronobiological modulation strategies are improving visualization. Microfluidic modeling could clarify the glymphatic-biomarker relationship; it may also advance precision medicine approaches for traumatic brain injury.

Background: Cerebral ischemia-reperfusion injury (CIRI) represents the most critical pathological event in the evolution of ischemic stroke (IS). Apoptosis is particularly important in CIRI pathophysiology. The interleukin-7 receptor (IL7R) is involved in various disease regulatory mechanisms; however, its specific role during CIRI remains unclear. We investigated the mechanistic function of IL7R in CIRI through a mouse model in vivo and through an astrocyte model in vitro.

Methods: C57BL/6 mice were randomly allocated to one of five groups: (1) sham; (2) transient middle cerebral artery occlusion (tMCAO); (3) tMCAO + IL7R treatment; (4) tMCAO + negative control (NC); or (5) tMCAO + IL7R + the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor (LY294002) (n = 3-7 per group) to evaluate the role of IL7R in CIRI. The in vitro study groups were (1) control; (2) oxygen-glucose deprivation/reoxygenation (OGD/R); (3) OGD/R + IL7R; (4) OGD/R + NC; and (5) OGD/R + IL7R + LY294002 groups. After IL7R overexpression was induced, the resulting changes in infarct volume, neurological score, cell viability, and expression of apoptosis-related proteins were assessed.

Results: IL7R overexpression significantly attenuated CIRI-induced apoptosis. In vivo, this intervention improved neurological function, alleviated cerebral edema, and decreased infarct volume in tMCAO mice. In vitro, after the overexpression of IL7R, flow cytometry analysis revealed a reduction in apoptosis rates post-OGD/R, whereas transmission electron microscopy revealed fewer morphological alterations associated with apoptosis. In addition, the level of Bcl-2-associated X protein (Bax) and cysteine-dependent aspartate-specific Protease-3 (caspase-3) were decreased, whereas that of B-cell lymphoma-2 (Bcl-2) was increased; these effects were reversed by LY294002.

Conclusion: Overexpression of IL7R was shown to alleviate CIRI by suppressing apoptosis. These findings indicate IL7R as a novel target for IS treatment.

Neurodegenerative diseases (NDDs) are closely linked to physiological conditions such as oxidative stress, neuroinflammation, neuronal cell death, and proteostatic failure, all of which are associated with cerebral trace-element imbalance. Recent research has highlighted the potential of trace-element-based interventions due to their diverse redox, anti-inflammatory, and pro-survival bioactivities. Leveraging nanotechnology to construct trace-element-based nanotherapeutics capable of crossing the blood-brain barrier, actively targeting neurons, and enabling on-demand payload release has emerged as a promising strategy, transforming empirical supplementation into a precision nanomedicine approach. These nanoplatforms have demonstrated significant effects in disease treatment. However, systematic studies on their application in NDD therapy remain limited. In this review, we provide a comprehensive overview of trace-element-based nanotherapeutics, exploring how trace-metal imbalances contribute to NDD development, nanoparticle construction, and the advantages of trace-element-based nanoparticles. Additionally, we discuss the physiological aspects of trace-element metabolism and inflammation in NDD treatment, offer recommendations for future research, and comprehensively discuss and systematically evaluate the safety of trace-element nanoparticles. In doing so, we provide a resource that will help to guide the design and development of nanotherapeutics for NDDs and assist researchers in this emerging field.