Molecular Neurobiology最新文献

Microglial polarization toward M1/M2 phenotypes is crucial in modulating neuroinflammation following spinal cord injury (SCI). This study aimed to investigate the role of interferon alpha-inducible protein 27-like 2A (Ifi27l2a) in regulating microglial polarization in SCI. The expression of Ifi27l2a were analyzed using single-cell RNA sequencing. C57BL/6 mice that underwent SCI were pretreated with adeno-associated virus (AAV) carrying sh-Ifi27l2a. In vitro, BV-2 cells were transfected with si-Ifi27l2a and stimulated with lipopolysaccharide (LPS). The effects of Ifi27l2a silencing were assessed through Basso Mouse Scale (BMS) scoring, inclined plane testing, hematoxylin and eosin (H&E) and Nissl staining, quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. Ifi27l2a expression was markedly upregulated in microglia of mice with SCI. AAV delivery of sh-Ifi27l2a in SCI mice improved motor function and decreased neuronal death, as evidenced by increased BMS score, greater inclined plane angles, and increased Nissl bodies. sh-Ifi27l2a downregulated the expression of the M1-type marker inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, while upregulating the M2 marker Arginase-1 and the anti-inflammatory cytokine IL-10. The effects of Ifi27l2a silencing on the M1/M2 polarization balance were confirmed in LPS-stimulated BV-2 cells. Bioinformatic prediction identified JAK2/STAT3 as a potential downstream signaling of Ifi27l2a. The modulatory effects of Ifi27l2a silencing on microglial polarization were partially mediated by JAK2/STAT3 signaling. Ifi27l2a expression was upregulated in the microglia of SCI mice. Silencing Ifi27l2a at the injury site suppressed M1 polarization while promoting M2 polarization, primarily through inhibition of the JAK2/STAT3 signaling pathway.

Autism spectrum disorder (ASD) is a multifactorial, neuro-psychiatric, and neurodevelopmental illness possessing impaired social, behavioral, and communicative presentations. Research suggested the important role of the gut-brain axis in ASD, especially related to gut dysbiosis and mitochondrial dysfunction. This review comprehensively summarizes the existing evidence of the association between gut microbiota, microbial metabolites, and mitochondrial dysfunction in ASD, comprising of clinical, experimental, and epidemiological data over the last decade. The focus was on the research that clarifies the gut-mitochondria crosstalk and role in ASD pathophysiology. ASD patients demonstrate a substantial shift in the variety of gut microbiota, such as a decrease in the number of beneficial microbes and the growth of pathogenic taxa. These changes affect the biosynthesis of major neuroactive metabolites executing immune modulation and neurotransmission. The review detects the microbial metabolites that regulate mitochondrial activity through mechanisms like vagus nerve, intestinal hormones, and immune signaling. The different mitochondrial signaling pathways were inhibited including AMPK, mTOR, and NF-κB. Preventive interventions that concentrate on modulation of the microbiome and mitochondria may present a prospective line of therapy. Nevertheless, uncovered gaps should be mentioned in future research, multi-omics studies, longitudinal studies, and the protocol to understand the components of gut-brain axis in ASD to develop personalized therapy.

Alzheimer's disease (AD) is characterized by the pathological accumulation of neurofibrillary tangles (NFTs) and amyloid plaques, with hyperphosphorylated tau protein playing a central role in the formation of NFTs. Among the various phosphorylation sites on tau, p-tau181, p-tau231, and p-tau217 have emerged as promising biomarkers for AD. In addition, given the complexity of tau modifications across multiple sites, recent studies have explored tau forms phosphorylated at several sites simultaneously, hypothesizing that multi-site phosphorylation may offer greater diagnostic value than single-site modifications. These biomarkers can be measured in plasma and cerebrospinal fluid (CSF) using immunoassays, and their levels can be correlated with neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). This review article comprehensively compares these three phosphorylation sites to evaluate their roles as biomarkers in AD, focusing on their diagnostic accuracy, utility in early detection, and potential for monitoring disease progression. Each biomarker offers unique advantages and disadvantages, which influence its applicability in both clinical and research settings. Further, the review also highlights the evolving nature of this field, emphasizing the need for standardized approaches and further research to validate these biomarkers across diverse populations and integrate them into routine clinical practice. By synthesizing current evidence, including recent validation of fully automated platforms for plasma p-tau, this article provides insights into the transformative potential of tau biomarkers for improving AD diagnosis and management. The FDA's clearance of a plasma p-tau217-based blood test in May 2025 represents a pivotal step toward accessible, non-invasive AD diagnostics. This development highlights the valuable role of tau as a potential biomarker for the disease.

High-mobility group box 1 (HMGB1) undergoes dynamic expression, release, and subcellular localization changes, and exerts distinct functions in the central nervous system, playing a crucial role in neuroinflammation and exacerbating autoimmune diseases. Although microglia exhibit elevated HMGB1 expression during experimental autoimmune encephalomyelitis (EAE), the precise roles of microglial-derived HMGB1 in the pathogenesis and progression of EAE remain largely unknown. In this study, we generated conditional knockout mice lacking HMGB1 in microglia to assess the role of HMGB1 in EAE progression. We found that depletion of microglial HMGB1 decreased morbidity, delayed the onset of symptoms, and reduced the severity of demyelination in EAE. Furthermore, EAE mice with a conditional knockout of HMGB1 in microglia exhibited decreased expression of CD3⁺ T cells and HMGB1-positive cells in the spinal cord. This resulted in a marked reduction in the number of activated microglia and an alteration in their morphology, thereby restoring the pro-/anti-inflammatory balance of microglia/macrophages; these effects were accompanied by the regulation of inflammatory factor expression and neuronal damage in EAE. Together, these results suggest that HMGB1 derived from microglia breaks the pro-/anti-inflammatory balance and aggravates neuroinflammation in EAE. We propose that targeting microglial HMGB1 could be an effective way to reduce neuroinflammation.

Glutamate-mediated excitotoxicity leads to mitochondrial dysfunction, apoptosis, and neuronal cell death. This study aims to investigate whether NPY2 receptors (NPY2R) and NPY5 receptors (NPY5R) enhance the effects of Apelin-13/APJ signaling pathways as modulatory cofactors in the neuroprotection provided by Apelin-13 against excitotoxic damage and in the prevention of learning-memory disorders. D-Glutamic acid-induced excitotoxicity was established in 42 male Sprague-Dawley rats (6-8 weeks, 200-250 g). Animals were randomly divided into six groups (n = 7); Control (C; 0.9% NaCl, i.p), D-Glutamic Acid (G; 4 mg/kg, i.p), Apelin-13 (A; 300 µg/kg, i.p), D-Glutamic Acid + Apelin-13 (GA), D-Glutamic Acid + Apelin-13 + NPY2R antagonist (GAN2; 1,5 mg/kg, i.p) and D-Glutamic Acid + Apelin-13 + NPY5R antagonist (GAN5; 1,5 mg/kg, i.p). Locomotor activity were evaluated with the Open Field (OFT), short/long-term memory and learning performance, allocentric-egocentric orientation were assesed with novel object recognition (NORT) and Morris water maze (MWM) tests. All parameters were normalized to the C group, and statistical significance between groups was assesed. In group G, a significant decrease (p < 0.001) in Extracellular Signal Regulatory Kinase (ERK1/2) and Protein Kinase B-1 (AKT-1) levels and an increase (p < 0.001) in Caspase-3 were observed. Oxidative parameters increased in the G and GAN2 groups. Antioxidant parameters were also elevated in GA and GAN5, similar to C and A groups. An increase in MWM latency to the target quadrant (p < 0.001) and a decrease in NORT discrimination index (p < 0.001) were found in the G and GAN2 groups compare to the C and A. Histochemical staining scores showed that the protection of Apelin-13 was mediated by NPY2R. In GAN2, blocking NPY2R reduces Apelin-13's neuroprotection, which is sustained only via NPY5R with limited effect. In GAN5, Apelin-13's protection was enhanced through NPY2R, as shown with NPY5R blockade. Accordingly, Apelin-13 exerts its neuroprotective effects primarily through NPY2R, its modulatory influence via NPY5R appears to be comparatively limited.

Cerebral ischemia-reperfusion (I/R) injury remains a major challenge in patients with ischemic stroke undergoing endovascular thrombectomy (EVT). Although selective intraarterial hypothermia has shown neuroprotective potential, its therapeutic efficacy is limited, highlighting the need for effective pharmacological adjuncts. This study investigated whether combining intracarotid hypothermia with Shenmai could synergistically enhance neuroprotection against cerebral I/R injury. Cold Shenmai (4 °C) or saline was infused into rat brain. Systemic toxicity was assessed by body weight, serum biochemistry, organ morphology, and indices. Brain toxicity was evaluated with 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), and Fluoro-Jade B (FJB) staining. Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO). Neuroprotection was assessed by TTC staining, neurological deficit score, rotarod, adhesive removal, and by H&E, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and Nissl staining. RNA sequencing explored mechanisms. Inflammatory cytokines were quantified by quantitative real-time polymerase chain reaction (qRT-PCR), while extracellular signal-regulated kinase (ERK) and nuclear factor kappa-B (NF-κB) signaling were examined by Western blot and immunofluorescence. The ERK inhibitor PD98059 verified mechanistic contributions. Cold Shenmai infusion showed no evidence of systemic or cerebral toxicity. Compared with cold saline, it significantly reduced infarct volume, improved neurological function and behavioral outcomes, and attenuated neuronal damage. Transcriptomic analysis revealed downregulation of pro-inflammatory pathways and reduced expression of microglial activation-related signaling. Mechanistically, cold Shenmai enhanced ERK1/2 phosphorylation, which was associated with reduced microglial marker expression and suppressed NF-κB P65 nuclear translocation. Importantly, these protective effects were markedly attenuated by the ERK1/2 inhibitor PD98059, indicating that ERK signaling plays a critical role in mediating the anti-inflammatory and neuroprotective effects of cold Shenmai during cerebral I/R injury. Intracarotid Shenmai with hypothermia synergistically attenuates cerebral I/R injury through ERK-mediated anti-inflammatory effects, including reduced microglial activation markers. These findings provide mechanistic preclinical evidence supporting Shenmai as an effective pharmacological adjunct to intraarterial hypothermia and suggest a promising therapeutic approach for mitigating reperfusion injury following EVT in acute ischemic stroke.

Hearing loss is a prevalent global health problem that most often arises from aging, noise exposure, ototoxic insults, or genetic defects. In addition to its well‑recognized social and economic burden, mounting evidence links hearing loss to neurological disorders such as Alzheimer's disease and dementia, underscoring the urgent need for effective curative strategies. Progress in regenerative therapies has been hindered by the limited capacity of mammalian auditory hair cells to regenerate, making a deep understanding of the underlying molecular pathology essential. The mechanistic target of rapamycin (mTOR), a master regulator of cell growth, metabolism, autophagy, and aging, has recently emerged as a key player in both auditory and neurological disorders. In this review, we summarize the current knowledge on how mTOR signaling shapes auditory cellular physiology, contributes to hearing disorder pathogenesis, and offers novel therapeutic entry points. We further explored the possibility that dysregulated mTOR activity may represent a missing mechanistic link between hearing loss and broader neurological disease processes.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, one of the most common types of dementia, accompanying severe learning and memory dysfunctions. In AD brains, the misfolded aggregation and deposits of amyloid-β (Aβ) and tau are frequently observed before the cognitive symptom onset; thus, trials for alleviation of these lesions are considered commensurate strategies with AD treatment. Additionally, increasing evidence suggests that misfolded and aggregated proteins induce the activation of microglia and astrocytes by the release of the inflammatory mediators via the activation of the inflammatory signaling cascade, which consequently contributes to AD pathogenesis. Here, we investigated the therapeutic potential of fucoxanthin, a compound derived from the microalgae Phaeodactylum tricornutum, in mitigating AD pathologies. Fucoxanthin was shown to inhibit the aggregation of Aβ and tau, converting their aggregates to monomeric forms. In the brain of APP/PS1 transgenic mice, fucoxanthin administration significantly reduced the levels of Aβ plaques and hyperphosphorylated tau and further ameliorated cognitive impairments by inhibiting the activation of microglia and astrocytes. Notably, fucoxanthin effectively regulated Aβ-induced NLRP3 inflammasome activation in astrocytes, reducing neuroinflammation associated with AD. Thus, our findings showing the multifaceted therapeutic mode of action of fucoxanthin against AD provide that fucoxanthin would have promising roles in the strategies of AD treatment.

Type 2 diabetes mellitus (T2DM) is a systemic metabolic disorder increasingly implicated in central nervous system (CNS) dysfunction, yet the molecular substrates underlying diabetes-induced dopaminergic (DAergic) dysregulation remain poorly defined. This study evaluated region-specific alterations in DAergic neurotransmission within the hippocampus, striatum, and prefrontal cortex, and their association with social behavioral deficits in diabetic mice. According to the weight and age of the animal, two groups were designated as the control group and the diabetes group. The control group was designated as group 1, and the diabetic group was designated as group 2. In group 2, diabetes was caused by injecting 50 mg/kg of streptozotocin for five consecutive days in them. The behavioural tests were performed after eight weeks of inducing diabetes. On the 60th day, from the striatum, hippocampus, and cortex, total RNA was taken out after the dissection. Real-time polymerase chain reaction was used to carry out expression analysis. STZ-induced diabetic mice showed normal sociability and social novelty preference but exhibited a marked decline in social recognition memory, indicating selective impairment of long-term social cognition. Region-specific dysregulation of dopaminergic signaling was evident, particularly in the striatum and cortex. These transcriptional alterations likely represent compensatory neuroadaptive mechanisms responding to oxidative and neuronal stress induced by diabetes, suggesting that T2DM-driven dopaminergic imbalance contributes to cognitive and neurobehavioral dysfunction. T2DM induces differential dysregulation of dopaminergic signaling across cortical and subcortical regions, contributing to selective deficits in social cognition. These findings highlight potential therapeutic targets for mitigating diabetes-associated neurobehavioral dysfunction.

Emerging evidence suggests that chronic infections may contribute to neurodegenerative diseases such as Alzheimer's disease (AD). One such infection is caused by Borrelia burgdorferi sensu lato (Bbsl), the spirochete complex responsible for Lyme disease, which can invade the central nervous system (CNS) and trigger Lyme neuroborreliosis (LNB). Bbsl infection is associated with persistent neuroinflammatory responses and immune evasion mechanisms, which may contribute to long-term neurological sequelae in a subset of patients. Neuroinflammation is increasingly recognized as a contributing factor in AD pathogenesis. This review examines proposed mechanistic overlaps between LNB and AD, focusing on the role of Bbsl-induced neuroinflammation driving amyloid-beta (Aβ) accumulation and tau pathology. We summarize evidence from in vitro, in vivo, and postmortem studies reporting assay-dependent co-localization of Borrelia with hallmark AD pathology in selected cases, alongside epidemiological studies that yield mixed results. While some studies suggest an association between Bbsl exposure and neurodegenerative risk, others report no clear correlation. Overall, current evidence indicates only an association, and a causal relationship between Bbsl infection and AD has not been established. Understanding this potential link may inform future mechanistic studies, biomarker development, and preventive strategies targeting chronic infection-driven neuroinflammation to address the hypothesis.