Pub Date : 2026-01-22DOI: 10.1007/s12035-026-05685-3
Kadriye Yagmur Oruc, Aykut Oruc, Ruhat Arslan, Furkan Pasa Diriarin, Murat Mengi, Gamze Tanriverdi, Karolin Yanar, Mediha Ozeren Eser, Gokhan Agturk, Ali Ihsan Sonkurt, Berkay Guler, Hakki Oktay Seymen
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.
{"title":"Apelin-13 confers Neuropeptide Y-mediated neuroprotection and preserves learning and allocentric memory in D-glutamic acid-induced excitotoxicity in rats.","authors":"Kadriye Yagmur Oruc, Aykut Oruc, Ruhat Arslan, Furkan Pasa Diriarin, Murat Mengi, Gamze Tanriverdi, Karolin Yanar, Mediha Ozeren Eser, Gokhan Agturk, Ali Ihsan Sonkurt, Berkay Guler, Hakki Oktay Seymen","doi":"10.1007/s12035-026-05685-3","DOIUrl":"10.1007/s12035-026-05685-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"387"},"PeriodicalIF":4.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
脑缺血再灌注(I/R)损伤仍然是缺血性卒中患者接受血管内取栓(EVT)的主要挑战。尽管选择性动脉内低温已显示出神经保护潜力,但其治疗效果有限,因此需要有效的药物辅助治疗。本研究探讨颈动脉内低温联合参麦是否能协同增强脑I/R损伤的神经保护作用。冷参麦(4℃)或生理盐水灌胃大鼠脑。以体重、血清生化、脏器形态及指标评价全身毒性。脑毒性评价采用2,3,5-三苯四唑氯(TTC)、苏木精和伊红(H&E)和氟玉B (FJB)染色。大脑中动脉闭塞(MCAO)致脑I/R损伤。通过TTC染色、神经功能缺损评分、rotarod、黏附去除、H&E、末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)和尼氏染色评估神经保护作用。RNA测序探索了机制。采用实时荧光定量聚合酶链反应(qRT-PCR)检测炎症因子,Western blot和免疫荧光检测细胞外信号调节激酶(ERK)和核因子κ b (NF-κB)信号。ERK抑制剂PD98059证实了其机制作用。冷参麦输注无系统性或脑毒性。与冷盐水相比,它显著减少了梗死体积,改善了神经功能和行为结果,减轻了神经元损伤。转录组学分析显示,促炎通路下调,小胶质细胞激活相关信号表达减少。机制上,冷参麦增强ERK1/2磷酸化,这与降低小胶质细胞标志物表达和抑制NF-κB P65核易位有关。重要的是,这些保护作用被ERK1/2抑制剂PD98059显著减弱,这表明ERK信号在脑I/R损伤中介导冷参麦的抗炎和神经保护作用中起关键作用。颈动脉内参麦联合低温治疗通过erk介导的抗炎作用协同减轻脑I/R损伤,包括减少小胶质细胞激活标志物。这些发现提供了临床前机制证据,支持参麦作为动脉低温治疗的有效药物辅助,并为减轻急性缺血性卒中EVT后再灌注损伤提供了有希望的治疗方法。
{"title":"Synergistic Neuroprotection of Combined Shenmai and Hypothermia in Cerebral Ischemia-Reperfusion Injury via ERK-Dependent Anti-inflammatory Effects.","authors":"Yuan Wang, Hangui Ren, Yufei Qiu, Rongchen Dai, Mengfan Liu, Shiting Mo, Yibo Zhang, Wang Fu, Qianqian Bi, Yongpeng Wang, Yunuo Zhou, Zhichao Xi, Hongxi Xu, Feng Wang","doi":"10.1007/s12035-026-05682-6","DOIUrl":"https://doi.org/10.1007/s12035-026-05682-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"384"},"PeriodicalIF":4.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"The mTOR Pathway in Hearing Disorders: Mechanistic Links to Aging, Regeneration, and Neurodegeneration.","authors":"Safura Pournajaf, Maryam Moghbel Baerz, Shahrokh Khoshsirat","doi":"10.1007/s12035-025-05653-3","DOIUrl":"https://doi.org/10.1007/s12035-025-05653-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"388"},"PeriodicalIF":4.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1007/s12035-026-05680-8
Na-Hyun Ahn, Sung-Chul Hong, Chi Rac Hong, Eun Ha Lee, Joo-Hee Lee, Su-Bin Choi, Jaewoon Jung, Yebeen Kim, Jung-Seok Kim, Keunwan Park, Yun Kyung Kim, YoungSoo Kim, Seung-Hoon Yang
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.
{"title":"Fucoxanthin Extracted from the Microalgae Phaeodactylum tricornutum Ameliorates Alzheimer's Pathologies with the Reduction of Aβ-Induced NLRP3 Inflammasome Activation in APP/PS1 Mice.","authors":"Na-Hyun Ahn, Sung-Chul Hong, Chi Rac Hong, Eun Ha Lee, Joo-Hee Lee, Su-Bin Choi, Jaewoon Jung, Yebeen Kim, Jung-Seok Kim, Keunwan Park, Yun Kyung Kim, YoungSoo Kim, Seung-Hoon Yang","doi":"10.1007/s12035-026-05680-8","DOIUrl":"https://doi.org/10.1007/s12035-026-05680-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"385"},"PeriodicalIF":4.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Assessment of Hippocampal, Prefrontal Cortical, and Striatal Dopaminergic Circuitry Underlying Altered Social Behavior in Diabetes.","authors":"Arun Parashar, Vineet Mehta, Udayabanu Malairaman, Muskan Thakur, Varsha Sharma","doi":"10.1007/s12035-026-05694-2","DOIUrl":"https://doi.org/10.1007/s12035-026-05694-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"386"},"PeriodicalIF":4.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1007/s12035-026-05676-4
Ria Ahuja, Ayleen Shaban, Jyotsna Chawla, Mayur S Parmar
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.
{"title":"Borrelia burgdorferi-Induced Neuroinflammation in Lyme Disease: A Potential Driver of Alzheimer's Disease Pathology?","authors":"Ria Ahuja, Ayleen Shaban, Jyotsna Chawla, Mayur S Parmar","doi":"10.1007/s12035-026-05676-4","DOIUrl":"https://doi.org/10.1007/s12035-026-05676-4","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"381"},"PeriodicalIF":4.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1007/s12035-026-05699-x
Rui Filipe Malheiro, Ana Catarina Costa, Catarina Pereira-Teixeira, Helena Carmo, Félix Carvalho, João Pedro Silva
Mitochondria are essential drivers of neuronal growth, differentiation, and overall brain development. Synthetic cannabinoids (SCs) have been shown to enhance neurite outgrowth in NG108-15 neuroblastoma x glioma cells through CB1 receptor activation, while disrupting mitochondrial function. Here, we demonstrated first-hand the impact of biologically-relevant concentrations (< 1μM) of ADB-FUBINACA (an SC commonly identified in drug seizures) on mitochondrial morphology and dynamics (i.e., fusion, fission and mobility) during the neurodifferentiation of NG108-15 cells. Our findings revealed that, during NG108-15 neurodifferentiation, ADB-FUBINACA reduced the mean mitochondrial area and perimeter by around 10%, while increasing mitochondrial circularity, and decreasing network branching and interconnectivity. Specifically, branch length per mitochondrion and branch junctions declined by 17 and 25% in the neurons' soma at the end of NG108-15 differentiation (after 72 h). Moreover, 1 nM and 1 µM ADB-FUBINACA markedly decreased the levels of mitochondrial fusion markers (Opa1 and Mfn2) and increased the levels of fission markers Drp1 and Fis1 at the same time point. The percentage of motile mitochondria in neurites also decreased at 72 h, while average speed and total run length per mobile mitochondrion remained unaffected, resulting in an accumulation of stationary mitochondria which may be important, for example, to support neurite extension. Collectively, these findings suggest that while ADB-FUBINACA promotes mitochondrial accumulation in neurites, potentially supporting the energy demands of developing neurites and influencing neurite outgrowth, in the long-term, the fragmentation of the mitochondrial network in the soma may compromise the maintenance of neurites, in terms of energy requirements.
{"title":"The Synthetic Cannabinoid ADB-FUBINACA Disrupts Mitochondrial Morphology and Dynamics during Neuronal Differentiation of NG108-15 Cells.","authors":"Rui Filipe Malheiro, Ana Catarina Costa, Catarina Pereira-Teixeira, Helena Carmo, Félix Carvalho, João Pedro Silva","doi":"10.1007/s12035-026-05699-x","DOIUrl":"10.1007/s12035-026-05699-x","url":null,"abstract":"<p><p>Mitochondria are essential drivers of neuronal growth, differentiation, and overall brain development. Synthetic cannabinoids (SCs) have been shown to enhance neurite outgrowth in NG108-15 neuroblastoma x glioma cells through CB1 receptor activation, while disrupting mitochondrial function. Here, we demonstrated first-hand the impact of biologically-relevant concentrations (< 1μM) of ADB-FUBINACA (an SC commonly identified in drug seizures) on mitochondrial morphology and dynamics (i.e., fusion, fission and mobility) during the neurodifferentiation of NG108-15 cells. Our findings revealed that, during NG108-15 neurodifferentiation, ADB-FUBINACA reduced the mean mitochondrial area and perimeter by around 10%, while increasing mitochondrial circularity, and decreasing network branching and interconnectivity. Specifically, branch length per mitochondrion and branch junctions declined by 17 and 25% in the neurons' soma at the end of NG108-15 differentiation (after 72 h). Moreover, 1 nM and 1 µM ADB-FUBINACA markedly decreased the levels of mitochondrial fusion markers (Opa1 and Mfn2) and increased the levels of fission markers Drp1 and Fis1 at the same time point. The percentage of motile mitochondria in neurites also decreased at 72 h, while average speed and total run length per mobile mitochondrion remained unaffected, resulting in an accumulation of stationary mitochondria which may be important, for example, to support neurite extension. Collectively, these findings suggest that while ADB-FUBINACA promotes mitochondrial accumulation in neurites, potentially supporting the energy demands of developing neurites and influencing neurite outgrowth, in the long-term, the fragmentation of the mitochondrial network in the soma may compromise the maintenance of neurites, in terms of energy requirements.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"382"},"PeriodicalIF":4.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1007/s12035-026-05700-7
Gökçe Ceren Kuşçu, Ezgi Tut, Çevik Gürel, Aylin Buhur, Özgün Selim Germiyan, Çığır Biray Avcı, Cem Güler, Ebru Şancı, Nefise Ülkü Karabay Yavaşoğlu, Altuğ Yavaşoğlu
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and mitochondrial dysfunction. Recent studies implicate the histone acetyltransferase GCN5 in regulating mitochondrial homeostasis and oxidative stress. This study investigated the therapeutic potential of GCN5 silencing via systemically administered siRNA-loaded niosomes in a rotenone-induced rat model of PD. Niosomes were prepared using the thin-film hydration method, and the most effective siRNA sequence was selected through real time quantitative PCR (RT-qPCR) and immunofluorescence in primary mesencephalic neurons. Adult male rats were divided into four groups (n = 24/group), and PD was induced with rotenone (2 mg/kg/day, s.c., for 35 days). Behavioral assessments, biochemical analyses, IVIS imaging, histopathology, immunohistochemistry, and RT-qPCR were conducted. IVIS confirmed brain accumulation of siRNA-niosomes within 3-5 h post-injection. GCN5 siRNA treatment significantly improved locomotor activity (p < 0.05), decreased MDA levels (p < 0.05), and restored SOD and dopamine levels (p < 0.05). Molecular findings showed decreased GCN5 and mitochondrial fission-related gene Drp-1 expression, increased expression of mitophagy and biogenesis markers (↑Parkin, ↑PINK1, ↑Mfn2, ↑PGC-1α), elevated TH expression, and reduced α-synuclein accumulation. Histological analysis revealed preserved midbrain cytoarchitecture and reduced neuronal damage. In conclusion, these findings highlight that epigenetic silencing of GCN5 via siRNA-loaded niosomal delivery provides neuroprotection in PD by modulating the expression of genes involved in mitochondrial dynamics, offering preclinical support for its development as a novel therapeutic strategy.
{"title":"Mitochondrial Dynamics-Related Gene Regulation by Epigenetic Suppression of GCN5 Exerts Neuroprotective Effects in Rotenone-Induced Parkinson's Disease Model.","authors":"Gökçe Ceren Kuşçu, Ezgi Tut, Çevik Gürel, Aylin Buhur, Özgün Selim Germiyan, Çığır Biray Avcı, Cem Güler, Ebru Şancı, Nefise Ülkü Karabay Yavaşoğlu, Altuğ Yavaşoğlu","doi":"10.1007/s12035-026-05700-7","DOIUrl":"https://doi.org/10.1007/s12035-026-05700-7","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and mitochondrial dysfunction. Recent studies implicate the histone acetyltransferase GCN5 in regulating mitochondrial homeostasis and oxidative stress. This study investigated the therapeutic potential of GCN5 silencing via systemically administered siRNA-loaded niosomes in a rotenone-induced rat model of PD. Niosomes were prepared using the thin-film hydration method, and the most effective siRNA sequence was selected through real time quantitative PCR (RT-qPCR) and immunofluorescence in primary mesencephalic neurons. Adult male rats were divided into four groups (n = 24/group), and PD was induced with rotenone (2 mg/kg/day, s.c., for 35 days). Behavioral assessments, biochemical analyses, IVIS imaging, histopathology, immunohistochemistry, and RT-qPCR were conducted. IVIS confirmed brain accumulation of siRNA-niosomes within 3-5 h post-injection. GCN5 siRNA treatment significantly improved locomotor activity (p < 0.05), decreased MDA levels (p < 0.05), and restored SOD and dopamine levels (p < 0.05). Molecular findings showed decreased GCN5 and mitochondrial fission-related gene Drp-1 expression, increased expression of mitophagy and biogenesis markers (↑Parkin, ↑PINK1, ↑Mfn2, ↑PGC-1α), elevated TH expression, and reduced α-synuclein accumulation. Histological analysis revealed preserved midbrain cytoarchitecture and reduced neuronal damage. In conclusion, these findings highlight that epigenetic silencing of GCN5 via siRNA-loaded niosomal delivery provides neuroprotection in PD by modulating the expression of genes involved in mitochondrial dynamics, offering preclinical support for its development as a novel therapeutic strategy.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"383"},"PeriodicalIF":4.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.
{"title":"α-Synuclein Deletion Leads to Hyposmia: due to Defective Autophagy Induced by Abnormal PI3K/mTOR Signaling Pathway in Olfactory Bulb.","authors":"Yuqing Shi, Huizhi Wang, Jing Chen, Jing Ren, Xiaohong Sun, Mingqin Qu, Tongfei Zhao, Chunlei Han, Junliang Yuan, Fangang Meng, Lingling Lu","doi":"10.1007/s12035-026-05686-2","DOIUrl":"https://doi.org/10.1007/s12035-026-05686-2","url":null,"abstract":"<p><p>α-Synuclein has been the center of focus in understanding synucleinopathies such as Parkinson's disease, amyotrophic lateral sclerosis, multiple system atrophy, dementia with Lewy bodies, for decades. Most researches focus on its pathology. However, its physiological function remains elusive, especially in olfactory system, one of the original sites to find α-synuclein accumulation in Parkinson's disease. In the present study, α-synuclein knockout (KO) mice were employed to study its physiological function. KO mice exhibited olfaction impairment with cell apoptosis in olfactory bulb. To identify molecules underlying olfactory dysfunction, we employed proteomics based on isobaric tags for relative and absolute quantification (iTRAQ). 188 differentially expressed proteins were identified between KO mice and its littermate control of wildtype mice. Bioinformatic analysis highlighted Phosphatidyl-inositol-3-kinase (PI3K) pathway. Hence, we examined its activation and found that both PI3K and its downstream, protein kinase B(AKT) is hyperactivated with α-synuclein deficiency. Mammalian target of Rapamycin (mTOR), a switch of autophagy, was activated followed by uncoordinated 51-like kinase 1, the autophagy initiator, inhibition. The specific substrate of autophagy, P62 was accumulated, indicating that autophagy was blocked. This blockade of autophagy led to Caspase 8 mediated apoptosis characterized by an increased ratio of B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) to BCL-2 (BAX/BCL-2), reduced mitochondrial complex I activity, and decreased mitochondrial membrane potential. To summarize, α-synuclein played roles in maintaining the normal structure and function of olfactory system. α-Synuclein deletion induced Caspase 8 mediated apoptosis due to the defective autophagy by PI3K/mTOR hyperactivation.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"378"},"PeriodicalIF":4.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1007/s12035-026-05688-0
Yijia Xu, Miaoran Zhang, Kaiping Zhou, Lei Wang
Temporal lobe epilepsy (TLE), one of the most prevalent focal epilepsies, is characterized by aberrant neuron and glial activation, yet the mechanisms driving microglia-astrocyte crosstalk remain elusive. To address this, we performed integrative single-nucleus RNA sequencing (snRNA-seq) analysis on surgically resected human brain tissue samples from a discovery cohort (4 TLE patients vs 4 controls) and a validation cohort (7 focal epilepsy cases vs the same controls). Using Seurat-based clustering, we identified 9 major cell types and further subclustered microglia and astrocytes. Cell-cell communication, gene regulatory networks, and pseudotime analysis were employed to explore the molecular mechanisms of microglia-astrocyte interactions. Results revealed significant expansion of both activated microglial and activated astrocytic subpopulations in TLE patients versus controls. The SPP1-CD44 axis emerged as the dominant pathway mediating their crosstalk, with reactive microglia as primary SPP1 senders and reactive astrocytes as CD44 receivers. The upstream regulators of SPP1-CD44 axis were subsequently explored, and 9 transcription factors (TFs) were identified as key regulators in reactive microglia. Pseudotime analysis further revealed a CD44-associated phenotypic shift from homeostatic to reactive astrocytes, characterized by progressive loss of synaptic regulatory functions and concurrent acquisition of neurotoxic properties during disease progression. Collectively, our multi-cohort snRNA-seq study reveals the SPP1-CD44 axis as a key mediator of neuroinflammatory pathology in TLE, linking microglial activation to astrocytic dysfunction. These findings broaden therapeutic strategies beyond neuronal targets, underscoring glial modulation as a promising adjunctive approach for epilepsy treatment.
{"title":"Single-Cell Dissection of the SPP1-CD44 Axis Reveals Microglia-Astrocyte Crosstalk Driving Neuroinflammation in Temporal Lobe Epilepsy.","authors":"Yijia Xu, Miaoran Zhang, Kaiping Zhou, Lei Wang","doi":"10.1007/s12035-026-05688-0","DOIUrl":"https://doi.org/10.1007/s12035-026-05688-0","url":null,"abstract":"<p><p>Temporal lobe epilepsy (TLE), one of the most prevalent focal epilepsies, is characterized by aberrant neuron and glial activation, yet the mechanisms driving microglia-astrocyte crosstalk remain elusive. To address this, we performed integrative single-nucleus RNA sequencing (snRNA-seq) analysis on surgically resected human brain tissue samples from a discovery cohort (4 TLE patients vs 4 controls) and a validation cohort (7 focal epilepsy cases vs the same controls). Using Seurat-based clustering, we identified 9 major cell types and further subclustered microglia and astrocytes. Cell-cell communication, gene regulatory networks, and pseudotime analysis were employed to explore the molecular mechanisms of microglia-astrocyte interactions. Results revealed significant expansion of both activated microglial and activated astrocytic subpopulations in TLE patients versus controls. The SPP1-CD44 axis emerged as the dominant pathway mediating their crosstalk, with reactive microglia as primary SPP1 senders and reactive astrocytes as CD44 receivers. The upstream regulators of SPP1-CD44 axis were subsequently explored, and 9 transcription factors (TFs) were identified as key regulators in reactive microglia. Pseudotime analysis further revealed a CD44-associated phenotypic shift from homeostatic to reactive astrocytes, characterized by progressive loss of synaptic regulatory functions and concurrent acquisition of neurotoxic properties during disease progression. Collectively, our multi-cohort snRNA-seq study reveals the SPP1-CD44 axis as a key mediator of neuroinflammatory pathology in TLE, linking microglial activation to astrocytic dysfunction. These findings broaden therapeutic strategies beyond neuronal targets, underscoring glial modulation as a promising adjunctive approach for epilepsy treatment.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":"63 1","pages":"376"},"PeriodicalIF":4.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}