Journal of integrative neuroscience最新文献

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.

Cardiac arrest (CA) is a leading cause of mortality worldwide, with cerebral injury resulting from hypoxia being its most significant complication. This condition is associated with low survival rates and unfavorable neurological prognosis. Cerebral injury following CA is a major contributor to both mortality and long-term disability. Recently, Targeted Temperature Management (TTM) has garnered considerable attention as a non-pharmacological treatment modality for brain protection, aiming to reduce hypoxia-induced damage and improve neurological outcomes following CA. This work aims to provide a comprehensive review of TTM following CA, focusing on its current status, underlying mechanisms, research advancements, and future prospects for clinical application.

Background: Post-stroke spastic hemiplegia (PSSH) frequently leads to severe motor dysfunction, with its primary pathology being spinal hyperexcitability arising from attenuated descending inhibition. We previously reported that acupuncture alleviated spastic hypertonia induced by middle cerebral artery occlusion (MCAO) via upregulating potassium-chloride cotransporter 2 (KCC2) expression. Cumulative evidence has indicated that N-methyl-D-aspartate receptor (NMDAR) can be a pivotal determinant of spinal excitability via modulating KCC2-mediated neuronal chloride homeostasis. The present study investigated whether acupuncture exerts its therapeutic effects through modulation of NMDAR-mediated activation of protein phosphatase 1 (PP1)/Calpain1-KCC2 pathway.

Methods: Multiple functional assessments, in vivo electrophysiological test, 2,3,5-triphenyl tetrazolium chloride (TTC) staining, immunofluorescence, quantitative real-time PCR (RT-qPCR), and Western blot were used.

Results: In the male MCAO rat model, assessments using the neurological-function score, muscle-tone scale, and footprint analysis demonstrated that acupuncture significantly attenuated spasticity and improved motor performance. H-reflex recordings and immediate early gene c-Fos (c-Fos) immunofluorescence indicated that acupuncture reduced hyperexcitability in spinal ventral horn. These observed effects of acupuncture were associated with its downregulation of N-methyl-D-aspartate receptor 1 (NMDAR1) expression and restoration of both the expression and function of KCC2 in spinal cord. Pharmacological interventions using NMDAR agonist and antagonist demonstrated that acupuncture upregulated KCC2 by inhibiting NMDAR-mediated activation of PP1 and Calpain1.

Conclusion: Acupuncture modulated the NMDAR-PP1/Calpain1-KCC2 pathway in the spinal cord to suppress neuronal hyperexcitability, thereby relieving spasticity and promoting motor function in rats with PSSH.