Experimental Neurology最新文献

Terminalia catappa L. (TC) has been traditionally used for its medicinal properties, including antioxidant and neuroprotective effects. Considering the increased vulnerability to cognitive decline and anxiety in aging, we investigated the potential impact of TC on anxiety-like behavior, memory, and oxidative stress in aged Wistar rats. Male Wistar rats were used, including young adults (70 days old) and aged animals (17 months old). The aged rats were allocated into three groups: control (n = 11), TC500 (n = 12), and TC1000 (n = 12). TC was administered by oral gavage at doses of 500 mg/kg or 1000 mg/kg for five weeks. Behavioral tests were conducted to assess anxiety: Open field, elevated plus maze, and light-dark box, and memory performance: Object recognition test and water maze, and oxidative stress markers were analyzed in brain tissue. TC-treated animals showed increased ambulation, rearing, grooming, time spent in open arms and central areas of the elevated plus maze, and increased head-dipping behavior, indicating anxiolytic-like effects. These findings were reinforced by greater time spent in the light compartment and higher transition rates in the light-dark box test, as well as increased exploration of novel objects in short- and long-term memory tasks. In the Morris water maze, the TC groups exhibited improved memory, demonstrated by shorter escape latency and greater total distance traveled. Both treatment groups showed reduced lipid peroxidation levels in brain tissue, suggesting decreased oxidative stress. These results indicate that TC may exert anxiolytic-like effects, enhance memory performance, and reduce oxidative stress in aged rats, supporting its potential as a neuroprotective agent in aging-related conditions.

Alzheimer's disease (AD) and diabetes mellitus (DM) represent escalating global health burdens, with epidemiological and clinical studies demonstrating a strong association between them. Diabetic patients face a significantly increased risk of AD, and poor glycemic control can accelerate AD progression. Chronic low-grade inflammation is increasingly recognized as a central mechanism bridging the two diseases. Triggering receptor expressed on myeloid cells 2 (TREM2), a key immune regulator, has emerged as a critical player in both AD and DM. In AD, TREM2 is specifically expressed on microglia, mediating neuroinflammatory and neurodegenerative processes while regulating both amyloid-β (Aβ) and Tau pathology. In DM, TREM2 contributes to insulin resistance and metabolic dysregulation. Genetic variants of TREM2 are established risk factors for AD, while altered TREM2 expression correlates with DM pathology. This review summarizes TREM2's structural and functional characteristics, its dual roles in AD and DM, and its potential as a therapeutic target. Elucidating these shared TREM2-mediated mechanisms may provide novel insights into the pathological interplay between AD and DM and inform precision therapeutic strategies.

The properties of central nervous system microglia adjust dynamically in response to various environmental signals, under both normal and disease conditions. However, the regulation of microglia homeostasis is not well understood. We hypothesize that the DEAD-box RNA helicase Ddx20 plays a key role in maintaining microglial homeostasis. To test this hypothesis, we generated mice with conditional deletion of Ddx20 in microglia using Iba1-iCre knock-in mice, and analyzed the effects of spinal cord injury and aging. Ddx20 ablation led to a drastic alteration of microglial morphology and a marked downregulation of gene networks involved in maintaining microglial identity, immune surveillance, and homeostatic functions; these effects become more prominent with spinal cord injury and aging. Our findings provide novel insights into the role of Ddx20 as a molecular regulator of microglial homeostasis and response to central nervous system injury.

The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhibitor, rapamycin, on central and peripheral immune profiles, proteasome activity, Aβ pathology, and spontaneous exploratory activity and place recognition in the 5xFAD mouse model of amyloid pathology. Using flow cytometry, we found that rapamycin induced changes in immune cell numbers and phenotypes in 5xFAD mice, notably a significant decrease of CD11c⁺ microglia in cortex and hippocampus of 5xFAD mice. This was associated with increased Aβ plaque load. Concomitantly, we observed a decrease in immunoproteasome content and activity. In peripheral blood, rapamycin treatment resulted in higher percentages of granulocytes, whereas splenic T lymphocytes were reduced. No changes in the open field and modified Y-maze tests were observed following rapamycin treatment in wild-type and 5xFAD mice. Our results reveal detrimental effects of rapamycin on amyloid plaque accumulation and CD11c⁺ disease-associated microglial subsets in cortex and hippocampus of 5xFAD mice, which is an important finding given two ongoing phase 2 clinical studies of rapamycin treatment in AD.

Cognitive resilience in Alzheimer's disease (AD) requires the maintenance of synaptic integrity despite progressive pathological insults. Reactive astrocytes can switch between neuroprotective and neurotoxic states, and their maladaptive transition significantly accelerates neurodegeneration, yet the molecular drivers of this shift remain elusive. Here, using published single-nucleus transcriptomic data, we identified the sialyltransferase St6galnac5 as a candidate regulator associated with reactive, pro-inflammatory astrocyte states. We further show that astrocyte-specific, AAV-mediated knockdown of St6galnac5 in female 3xTg-AD mice improves spatial learning, memory and anxiety-like behaviors. Neuropathological assessment revealed that this functional recovery was underpinned by a marked reduction in amyloid-β and tau pathologies, alongside the preservation of synaptic integrity. Consistent with a shift toward a less inflammatory astrocyte state, St6galnac5 knockdown decreased A1-associated markers and increased A2-associated markers in vitro and alleviated neurite outgrowth deficits in neuron-astrocyte co-culture. Together, our findings identify St6galnac5 as a critical molecular switch driving astrocytic dysfunction in AD, and further propose that targeted inhibition of this sialylation pathway represents a viable strategy to bolster astrocytic resilience and slow disease progression.

Traumatic brain injury (TBI) remains a major cause of mortality and long-term neurological disability worldwide, with secondary brain injury playing a critical role in disease progression. Increasing evidence indicates that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is a key contributor to secondary neuronal damage after TBI. This review systematically summarizes the core mechanisms of ferroptosis in TBI, focusing on blood-brain barrier (BBB) disruption-associated iron dysregulation, polyunsaturated fatty acids (PUFAs)-driven lipid peroxidation, and dysfunction of the glutathione-glutathione peroxidase 4 (GSH-GPX4) axis. We further highlight the extensive crosstalk between ferroptosis and other regulated cell death pathways, including apoptosis, necroptosis, and pyroptosis, mediated by shared upstream triggers and key molecular nodes. Ferroptosis is discussed in a stage-dependent manner across the acute, subacute, and chronic phases of TBI. Emerging ferroptosis-targeted therapeutic strategies, including ferroptosis inhibitors, traditional Chinese medicine (TCM)-derived compounds, gene therapy, and nanomaterial-based delivery systems, are critically reviewed. Finally, current translational challenges and future perspectives for ferroptosis-targeted precision therapy in TBI are discussed.

Background: Hyperhomocysteinemia (HHcy) is an important risk factor for Alzheimer's disease (AD), but its differential effects on tau pathology and beta-amyloid (Aβ) deposition, as well as the key mediating molecules involved, remain unclear. This study investigates how HHcy influences AD pathology and examines whether interleukin-1β (IL-1β) neutralization can mitigate HHcy-accelerated neurodegeneration.

Methods: Female 12-month-old 3 × Tg-AD mice were supplemented with methionine water for 7 weeks to induce HHcy. Brain tissues were analyzed for Aβ deposition, tau phosphorylation, oligomerization, and neurofibrillary tangle formation using ELISA, immunohistochemistry, Western blot, and Thioflavin S staining. To assess the role of IL-1β, HHcy-AD mice were treated with an anti-IL-1β monoclonal antibody (mAb; 100 μg, twice weekly for two weeks). Moreover, behavioral performance was evaluated using the Morris water maze for the effect of IL-1β neutralization.

Results: HHcy significantly exacerbated tau pathology, increasing oligomeric tau levels, hyperphosphorylation (AT-8, Ser396, Thr231), and neurofibrillary tangles, particularly in the cortex. In contrast, HHcy had minimal effects on Aβ deposition, only increasing insoluble Aβ1-40. Anti-IL-1β mAb treatment reduced tau phosphorylation and oligomerization, coinciding with inactivation of hippocampal GSK3β (increased p-Ser9). The mAb also improved cognitive function but showed selective effects on Aβ pathology and differentially modulated glial responses across brain regions.

Conclusion: HHcy preferentially exacerbates tauopathy rather than amyloidosis in 3 × Tg-AD mice. IL-1β neutralization ameliorates tau-related pathology and cognitive deficits, likely through regional suppression of GSK3β activity, highlighting its potential as a therapeutic strategy for tau-focused AD interventions.

The disruption or increased permeability of the blood-brain barrier (BBB) results in dysregulated autoantibody profiles in Alzheimer's disease (AD) patients. Naturally occurring antibodies against ASC (NAbs-ASC), which are present in human blood, can block the ability of ASC specks to seed Aβ aggregation. However, the characteristics and functions of NAbs-ASC in AD remain unclear. In this study, we found that plasma levels of NAbs-ASC were reduced in AD patients and showed negative correlation with the severity of cognitive impairment and with plasma Aβ42/40 ratios. NAbs-ASC treatment reduced Aβ production and attenuated Aβ-induced cytotoxicity in AD cell models. Furthermore, passive immunization with NAbs-ASC or active immunization with ASC peptides improved cognitive function, attenuated Aβ deposition, reduced Tau phosphorylation, inhibited neuroinflammation and apoptosis, and improved synaptic plasticity in APP/PS1 mice. These findings support that NAbs-ASC maybe important physiological protective factors for AD, and that immunotherapy targeting ASC may be a potential therapeutic intervention for the disease.

Concussive brain injury is a risk factor for anxiety disorders. Pre-clinical models demonstrate that concussion increases passive fear responses, such as conditioned freezing, yet provide limited insight to active responses like avoidance of perceived threats. This is important because persistent avoidance is characteristic of anxiety disorders. Moreover, brain injury can induce an imbalance of the gut microbiome, which can alter emotions. Adult male rats were trained on a platform-mediated avoidance task where they learned to step onto a platform to avoid a foot shock following a conditioned auditory tone. A sucrose reward was provided via a lever press that is opposite to the platform. Next, closed head injury was delivered to produce a mild concussion. After recovery, separate cohorts of rats were tested to dissociate between changes in avoidance expression and extinction-related processes. Cellular activity was assessed using c-Fos immunohistochemistry in brain regions implicated in avoidance: amygdala, medial prefrontal cortex, insular cortex, ventral striatum, and ventral hippocampus. Fecal pellets were collected to extract genetic material to identify potential changes in populations of bacteria in the gut microbiome. Closed head injury induced persistent avoidance by impairing extinction. Injured rats showed decreased activity in the basomedial amygdala and the CA1 subregion of the ventral hippocampus, increased activity in the rostral insular cortex and ventral striatum, and no change in the medial prefrontal cortex. Closed head injury did not induce changes in gut microbiota. Understanding mechanisms of concussion-induced avoidance is crucial for developing rehabilitation strategies for mental health disorders impacted by brain injury.