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 inv...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 a...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 respon...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.
BACKGROUND: Recent advances in gut-brain axis research have provided new insights into traumatic brain injury (TBI) treatment. Bifidobacterium longum subsp. infantis (B. infantis) has been demonstrated to reduce neuronal...BACKGROUND: Recent advances in gut-brain axis research have provided new insights into traumatic brain injury (TBI) treatment. Bifidobacterium longum subsp. infantis (B. infantis) has been demonstrated to reduce neuronal damage and alleviate cognitive symptoms in neurodegenerative diseases, yet its protective effect against TBI-induced cognitive impairment remains unclear. OBJECTIVE: To investigate whether B. infantis can alleviate TBI-induced cognitive impairment in mice and explore its underlying mechanisms. METHODS: Ninety SPF-grade C57BL/6 mice were randomly divided into sham-operated, TBI + saline, and TBI + B. infantis groups. A mild TBI model was established via controlled cortical impact (CCI). Mice in the TBI + B. infantis group received 150 μL of B. infantis suspension (10 CFU/mL) by gavage for 14 days before and 14 days after TBI; the other two groups received normal saline. Neurological function, pain sensitivity, and cognitive function were evaluated using behavioral tests. Histological, molecular biological, and biochemical analyses were performed to detect blood-brain barrier (BBB) integrity, hippocampal oxidative stress/inflammation, intestinal barrier function, and levels of trimethylamine N-oxide (TMAO) and methionine sulfoxide reductase A (MsrA). RESULTS: B. infantis significantly improved TBI-induced neurological deficits, hyperalgesia, and cognitive impairment. Mechanistically, it directly protected the central nervous system by maintaining BBB integrity (promoting the expression of tight junction proteins occludin and ZO-1) and inhibiting hippocampal oxidative stress (reducing ROS levels) and inflammation (suppressing IL-1β, IL-6, and TNF-α expression). Indirectly, it repaired intestinal barrier integrity (reducing serum D-lactate levels and upregulating occludin expression), inhibited intestinal inflammation (suppressing IL-6 expression), regulated TMAO metabolism (reducing serum and cerebrospinal fluid TMAO levels), and restored hippocampal MsrA expression. CONCLUSIONS: B. infantis exerts a protective effect against TBI through direct protection of the central nervous system and indirect regulation of intestinal homeostasis, providing a new candidate for adjuvant treatment of TBI and advancing gut-brain axis research in neurological diseases.
Traumatic brain injury (TBI) is frequently followed by persistent affective symptoms. Dysregulation of monoaminergic and galanin signalling has been implicated but it is unclear whether such changes generalize across dis...Traumatic brain injury (TBI) is frequently followed by persistent affective symptoms. Dysregulation of monoaminergic and galanin signalling has been implicated but it is unclear whether such changes generalize across distinct biomechanical injury modes. Here we examined a rotational head-acceleration model of mild-moderate injury and directly compared radioactive in situ hybridization (rISH) with a non-radioactive method, alongside immunohistochemistry (IHC), in adult male rats. We quantified transcripts and proteins/peptides of tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2), and galanin in locus coeruleus (LC) and dorsal raphe nucleus (DRN) and assessed the neuronal stress marker activating transcription factor-3 (ATF3). rISH revealed a rapid, bilateral rise of TH and galanin mRNA in LC at one day post-injury (dpi) and transient increases of TPH2 and galanin mRNA at 1 dpi in mid-DRN. Non-radioactive ISH confirmed these patterns, although modest temporal differences were observed. Peptide measurements showed a similar pattern of increase as their transcripts: TH- and galanin-immunoreactivity in LC increased at 3 dpi, and galanin also rose at 7 dpi in DRN, while TPH2 remained stable. Finally, ATF3 was robustly induced in LC neuronal nuclei at 1 dpi and remained elevated thereafter, indicating activation of a conserved stress response and possible axonal injury. These findings demonstrate that rotational head acceleration triggers selective, time-dependent modulation of monoaminergic and galanin signalling - paralleling prior blast models and confirm ATF3 as an informative marker of injury-activated neuronal states. The concordance across injury models highlights the monoamine and galanin systems as translatable targets for mitigating post-injury affective disturbances.
Adolescent experiences profoundly shape brain development and cognition. Environmental enrichment (EE) and social isolation (SI) represent opposing forms of stimulation and deprivation, yet the metabolic mechanisms conne...Adolescent experiences profoundly shape brain development and cognition. Environmental enrichment (EE) and social isolation (SI) represent opposing forms of stimulation and deprivation, yet the metabolic mechanisms connecting these conditions to cognitive outcomes remain poorly defined. In this study, we investigated how EE and SI during adolescence (PND 21-49) influence hippocampal metabolism and cognition in adult C57BL/6 mice. Behaviorally, SI impaired working and recognition memory, as reflected by reduced spontaneous alternation in the Y-maze and diminished novelty discrimination in the novel location and novel object recognition tasks. In contrast, EE mice showed preserved performance across these cognitive domains. Untargeted hippocampal metabolomics revealed clear group separation and showed that differential metabolites were overrepresented in glycerophospholipid-related classes. Consistently, KEGG pathway enrichment repeatedly highlighted glycerophospholipid metabolism along with membrane-associated signaling pathways. Correlation and network analyses further identified a tightly interconnected phospholipid module as a principal axis of between-group divergence, involving coordinated shifts across phosphatidylcholines, phosphatidylethanolamines, and lysophospholipids. To provide signaling-level support, we examined key components of the ERK-cPLA2 axis along with a synaptic protein marker in the hippocampus. SI mice exhibited reduced p-ERK/ERK ratios, elevated p-cPLA2 /cPLA2, and decreased PSD-95 expression, whereas EE mice showed higher p-ERK/ERK and a modest increase in p-cPLA2 /cPLA2 relative to SE controls. Together, these findings suggest that adolescent social experiences shape enduring hippocampal phospholipid turnover states that are coupled to plasticity-related signaling, providing a molecular and metabolic framework for experience-associated differences in memory.
Anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis often leads to long-term cognitive impairments, including deficits in executive function, even after acute symptoms resolution, but the underlying mechanisms remain...Anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis often leads to long-term cognitive impairments, including deficits in executive function, even after acute symptoms resolution, but the underlying mechanisms remain unclear. To explore this, a murine model was established via 14-day intracerebroventricular (ICV) infusion of anti-GluN1 IgG. Mice exhibited deficits in cognitive flexibility and short-term recognition memory, as evidenced by impaired performance in reversal learning and in the novel object recognition test, while spatial learning and anxiety-related behaviors were spared. Molecular analyses revealed decreased expression of GluN1 and GABAergic markers (GAD67, vGat) in the medial prefrontal cortex (mPFC). This disinhibition likely underlies the increased recruitment of excitatory neurons in the mPFC as suggested by the c-Fos expression, which may contribute to the cognitive rigidity in anti-GluN1 IgG-infused mice. Moreover, ex vivo electrophysiological recordings from mPFC pyramidal neurons showed increased sensitivity of spike generation together with diminished inhibitory synaptic input in anti-GluN1 IgG-infused mice. Together, these findings point to mPFC dysfunction, possibly involving GABAergic disruption and local disinhibition, as a candidate mechanism contributing to persistent cognitive rigidity in NMDAR antibody-associated encephalitis.
INTRODUCTION: A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (MAEL), a gene involved in regulation of DNA transposon activity and genome structure, as a transcriptome-w...INTRODUCTION: A prior integrative, multi-omics human genetics and functional genomics study identified maelstrom (MAEL), a gene involved in regulation of DNA transposon activity and genome structure, as a transcriptome-wide predictor of hydrocephalus (HC) in the brain cortex. However, the developmental timing, cell-type specificity, evolutionary conservation, and direct measurement of MAEL expression in human HC cortex remain unknown. OBJECTIVE: To characterize the evolutionary origin and developmental, cell-type specificity, and temporal expression patterns of MAEL in the developing human brain and to measure MAEL expression in primary human HC cortical tissue. METHODS: Ensembl was used to delineate the evolution and taxonomy of MAEL across species. Analysis of single-nucleus RNA sequencing (snRNA-seq) of 49 brain regions across pre- and post-natal timescales from the Developing Human Brain Atlas (Allen Institute) identified temporal and spatial MAEL expression patterns. We quantified MAEL expression in primary cortical brain tissue obtained during the surgical treatment of HC via snRNA-seq. RESULTS: We performed taxonomic gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in vitro and in vivo across species. We find that MAEL is among the top 0.01% human-specific genes and < 50% sequence homology among commonly used model organisms with highly divergent functions, necessitating mechanistic validation in human tissue. snRNA-seq of the non-disease prenatal human brain identified MAEL expression enriched in cortical excitatory neurons, which was recapitulated in primary HC brain tissue obtained during HC surgery. Finally, using snRNA-seq of primary HC brain tissue, we functionally validated reduced MAEL expression, consistent with a prior human TWAS analysis. CONCLUSIONS: Our findings extend prior genetic association data by defining the developmental and cellular context of MAEL expression in the human brain and by providing direct evidence of reduced MAEL expression in the human HC cortex. While these data support a plausible role of MAEL in HC pathobiology, further mechanistic studies are needed to prove causality.
BACKGROUND: Obstructive sleep apnea (OSA) is linked to metabolic dysfunction, but the role of chronic intermittent hypoxia (CIH)-induced mitochondrial apoptosis remains unclear. This study investigated whether CIH-induce...BACKGROUND: Obstructive sleep apnea (OSA) is linked to metabolic dysfunction, but the role of chronic intermittent hypoxia (CIH)-induced mitochondrial apoptosis remains unclear. This study investigated whether CIH-induced lung apoptosis involves gut microbiota and metabolite changes. METHODS: Mice exposed to CIH were analyzed using 16S rRNA sequencing and GC-MS metabolomics. Apoptosis markers (Drp1, BAX, Bcl-2, Caspase-3) were assessed via Western blot, immunohistochemistry, TUNEL, and electron microscopy. RESULTS: (1) CIH disrupted fatty acid metabolism (e.g., decreased arachidonic acid, increased nervonic acid), reversible with Mdivi-1 (mitochondrial fission inhibitor). (2) CIH altered gut microbiota, partially restored by Mdivi-1. (3) KEGG analysis revealed apoptosis, autophagy, and P53 pathway changes. (4) CIH reduced mouse weight and cognitive performance; Mdivi-1 improved these. (5) CIH increased BAX/Caspase-3 and decreased Bcl-2, worsening mitochondrial damage-exacerbated by CCCP (apoptosis inducer) but mitigated by Mdivi-1. CONCLUSIONS: Mdivi-1 alleviated CIH-induced gut dysbiosis, apoptosis, and mitochondrial damage, while CCCP worsened these effects. Gut microbiota and metabolic changes may mediate CIH-induced lung apoptosis.
BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effect...BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated. METHODS: Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise. RESULTS: Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU cells) proliferation, promoting differentiation into immature neurons (BrdUDCX cells), and maintaining newborn astrocytes (BrdUGFAP cells). Forced/combined exercise sustained immature neurons (DCX cells), and forced exercise alone significantly elevated mature newborn neurons (BrdUNeuN cells). Neuroprotective mechanisms may involve the modality-specific BDNF-TrkB signaling and BAX-dependent apoptosis regulation. Exercise-induced metabolites (amino acid homeostasis, energy provision, oxidative defense) strongly correlated with neurogenesis and neural function. In AD patients, acute voluntary exercise was associated with enhanced left prefrontal cortex activity, whereas acute forced exercise increased bilateral motor cortex activation. CONCLUSIONS: Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology.
Cognitive dysfunction is the main clinical feature of Alzheimer's disease (AD), and oxidative stress is considered a critical contributor to AD pathogenesis. Sulforaphane (SFN), an aliphatic isothiocyanate predominantly...Cognitive dysfunction is the main clinical feature of Alzheimer's disease (AD), and oxidative stress is considered a critical contributor to AD pathogenesis. Sulforaphane (SFN), an aliphatic isothiocyanate predominantly derived from cruciferous vegetables, has been reported to exert antioxidant and neuroprotective effects; however, its impact on synaptic plasticity and the underlying electrophysiological mechanisms in AD remain unclear. In this study, ten-month-old male APPswe/PS1dE9 double transgenic (APP/PS1) mice and wild-type (WT) littermates were randomized to four groups (WT + saline, WT + SFN, APP/PS1 + saline, and APP/PS1 + SFN). SFN was administered at 10 mg kgvia intraperitoneal injection for 30 d in vivo and 1 μM concentration in vitro. Then, we investigated whether SFN improves cognition by restoring hippocampal synaptic plasticity in APP/PS1 mice. It was suggested that SFN administration significantly attenuated Aβ₁₋₄₂-induced oxidative damage in vitro and improved spatial learning and reference memory deficits in APP/PS1 mice. Bioinformatics analysis suggested that SFN modulated synapse-related pathways associated with AD. Consistent with these findings, electrophysiological recordings demonstrated that SFN alleviated hippocampal long-term potentiation (LTP) impairment. Moreover, SFN increased the expression of synaptic proteins PSD-95 and synaptophysin and enhanced dendritic complexity and dendritic spine density in the hippocampal CA1 region, as assessed by immunoblotting and Golgi staining. Together, these results indicated that SFN ameliorated cognitive deficits in AD mice by alleviating LTP inhibition and restoring synaptic structural integrity, supporting a role for synaptic plasticity in the neuroprotective effects of SFN.