Pain is the most common non-motor manifestation of Parkinson's disease (PD), affecting the quality of life for patients. Nav1.6 is the most abundant subtype of voltage-gated sodium channels (VGSCs) in the brain of adult mammals. Here we investigated the expression patterns of Nav1.6 in the ventral posterolateral (VPL) nucleus of the thalamus and its involvement in the development of hyperalgesia in 6-hydroxydopamine (6-OHDA)-lesioned rats. The results showed a significant increase in Nav1.6 expression in reactive astrocytes of the ipsilateral VPL in 6-OHDA-lesioned rats at 4 weeks post-injection. Moreover, 6-OHDA-lesioned rats exhibited mechanical hyperalgesia, but did not display thermal hyperalgesia in the ipsilateral paw at the same time point. The down-regulation of Nav1.6 in the ipsilateral VPL can reduce mechanical hyperalgesia and improve sensorimotor impairments in 6-OHDA- lesioned rats. Furthermore, the analysis of local field potentials (LFPs) revealed that the increased Nav1.6 may participate in abnormal synchronized oscillations within the thalamocortical loop in 6-OHDA-lesioned rats. These findings suggest that the altered expression of Nav1.6 in astrocytes of the VPL may play an important role in the abnormal processing of pain within the thalamocortical circuit, contributing to the formation of mechanical hyperalgesia in animal models of PD.
{"title":"Upregulation of Nav1.6 expression in the ventral posterolateral nucleus of thalamus contributes to hyperalgesia in a model of Parkinson's disease","authors":"Zhiwei Li, Jiamin Luo, Chengjiyuan Li, Hongyan Zhu","doi":"10.1016/j.expneurol.2024.115032","DOIUrl":"10.1016/j.expneurol.2024.115032","url":null,"abstract":"<div><div>Pain is the most common non-motor manifestation of Parkinson's disease (PD), affecting the quality of life for patients. Nav1.6 is the most abundant subtype of voltage-gated sodium channels (VGSCs) in the brain of adult mammals. Here we investigated the expression patterns of Nav1.6 in the ventral posterolateral (VPL) nucleus of the thalamus and its involvement in the development of hyperalgesia in 6-hydroxydopamine (6-OHDA)-lesioned rats. The results showed a significant increase in Nav1.6 expression in reactive astrocytes of the ipsilateral VPL in 6-OHDA-lesioned rats at 4 weeks post-injection. Moreover, 6-OHDA-lesioned rats exhibited mechanical hyperalgesia, but did not display thermal hyperalgesia in the ipsilateral paw at the same time point. The down-regulation of Nav1.6 in the ipsilateral VPL can reduce mechanical hyperalgesia and improve sensorimotor impairments in 6-OHDA- lesioned rats. Furthermore, the analysis of local field potentials (LFPs) revealed that the increased Nav1.6 may participate in abnormal synchronized oscillations within the thalamocortical loop in 6-OHDA-lesioned rats. These findings suggest that the altered expression of Nav1.6 in astrocytes of the VPL may play an important role in the abnormal processing of pain within the thalamocortical circuit, contributing to the formation of mechanical hyperalgesia in animal models of PD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115032"},"PeriodicalIF":4.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555015","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 : 2024-10-28DOI: 10.1016/j.expneurol.2024.115028
Xinlei Zhang , Lulu Wang , Chen Xu , Heng Wang , An Yan , Qingmeng Zheng , Ke Wang , Xiaomeng Qiao
Alcohol abuse damages the brain and triggers cognitive impairment. Intestinal dysbiosis has recently been shown to be involved in psychiatric disorders, which suggests the possibility of intestine-to-brain interactions in the development of alcohol abuse. In this study, chronic intermittent alcohol exposure (CIAE) model was established in C57BL/6 male mice and the spatial memory were detected by Barnes maze (n = 16/group). The fecal microbiota and its metabolites were detected by 16S rDNA sequencing and non-target liquid chromatograph mass spectrometer (LC-MS) (n = 8/group). Effects of alcohol on intestinal barrier and blood-brain barrier (BBB) permeability were detected by Evens blue leakage assay (n = 4/group), and the activation state of microglia and TLR4 expression were conducted by immunofluorescence co-localization (n = 4/group). The morphological changes of microglia were analyzed with Image J Analyze Skeleton software, and the protein levels of TLR4 and inflammatory factors were detected by Western Blot (n = 8/group). Results indicated that alcohol alters the components of fecal microbiota and metabolites, and damages the intestinal barrier and BBB, leading to spatial memory impairment in mice. By giving mice specific prebiotics (n = 16/group), we pointed out that increased endotoxin coming from Gram negative bacteria such as lipopolysaccharides (LPS) cross the BBB to activate microglia and inflammatory pathways in the prefrontal cortical (PFC) and hippocampus (HIP), releasing inflammatory factors and resulting in neuroinflammation. Thus, the fecal microbiota seems to be a potential target in the management of alcoholic brain disease.
{"title":"Intestinal dysbiosis causes spatial memory impairment in alcohol-exposed male mice by inducing neuroinflammation","authors":"Xinlei Zhang , Lulu Wang , Chen Xu , Heng Wang , An Yan , Qingmeng Zheng , Ke Wang , Xiaomeng Qiao","doi":"10.1016/j.expneurol.2024.115028","DOIUrl":"10.1016/j.expneurol.2024.115028","url":null,"abstract":"<div><div>Alcohol abuse damages the brain and triggers cognitive impairment. Intestinal dysbiosis has recently been shown to be involved in psychiatric disorders, which suggests the possibility of intestine-to-brain interactions in the development of alcohol abuse. In this study, chronic intermittent alcohol exposure (CIAE) model was established in C57BL/6 male mice and the spatial memory were detected by Barnes maze (<em>n</em> = 16/group). The fecal microbiota and its metabolites were detected by 16S rDNA sequencing and non-target liquid chromatograph mass spectrometer (LC-MS) (<em>n</em> = 8/group). Effects of alcohol on intestinal barrier and blood-brain barrier (BBB) permeability were detected by Evens blue leakage assay (<em>n</em> = 4/group), and the activation state of microglia and TLR4 expression were conducted by immunofluorescence co-localization (<em>n</em> = 4/group). The morphological changes of microglia were analyzed with Image J Analyze Skeleton software, and the protein levels of TLR4 and inflammatory factors were detected by Western Blot (<em>n</em> = 8/group). Results indicated that alcohol alters the components of fecal microbiota and metabolites, and damages the intestinal barrier and BBB, leading to spatial memory impairment in mice. By giving mice specific prebiotics (<em>n</em> = 16/group), we pointed out that increased endotoxin coming from Gram negative bacteria such as lipopolysaccharides (LPS) cross the BBB to activate microglia and inflammatory pathways in the prefrontal cortical (PFC) and hippocampus (HIP), releasing inflammatory factors and resulting in neuroinflammation. Thus, the fecal microbiota seems to be a potential target in the management of alcoholic brain disease.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115028"},"PeriodicalIF":4.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555013","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 : 2024-10-28DOI: 10.1016/j.expneurol.2024.115027
Panpan Zhao , Wei Zhang , Xinyu Zhou , Yikun Zhao , Aimin Li , Yong Sun
Sepsis-related systemic inflammation is a deadly condition with high rates of morbidity and mortality. There is evidence that sepsis affects the brain, and the most frequent organ dysfunction linked to sepsis is sepsis-associated encephalopathy. Sepsis-related brain damage can drastically reduce a patient's chances of survival. However, a specific treatment for sepsis-associated encephalopathy is not currently available. Consequently, to treat the brain damage caused by sepsis, investigating novel therapeutic strategies is imperative. After establishing the CLP-induced mouse SAE model, we treated the mice with Gyp-XLIX and evaluated apoptosis, neuroinflammation, brain damage, and oxidative stress in the brain tissue of each group of mice. Furthermore, the protective effects of Gyp-XLIX on LPS-treated BV-2 cells were assessed. We discovered that Gyp-XLIX treatment increased the survival rate of CLP-treated mice, alleviated SAE-related cerebral nerve abnormalities, and decreased blood–brain barrier breakdown, all of which could better preserve brain tissue in vivo. Furthermore, we identified associated proteins and found that Gyp-XLIX may reduce oxidative stress, cell apoptosis, and inflammation in the brain tissues of SAE mice. This observation was further validated in vitro. We established that Gyp-XLIX alleviates SAE by targeting PPAR-α. These findings may be important for the clinical applicability of Gyp-XLIX in SAE treatment. We found that Gyp-XLIX can alleviate brain injury in SAE by targeting PPAR-α and is a potential protective agent for SAE.
{"title":"Gypenoside XLIX alleviates sepsis-associated encephalopathy by targeting PPAR-α","authors":"Panpan Zhao , Wei Zhang , Xinyu Zhou , Yikun Zhao , Aimin Li , Yong Sun","doi":"10.1016/j.expneurol.2024.115027","DOIUrl":"10.1016/j.expneurol.2024.115027","url":null,"abstract":"<div><div>Sepsis-related systemic inflammation is a deadly condition with high rates of morbidity and mortality. There is evidence that sepsis affects the brain, and the most frequent organ dysfunction linked to sepsis is sepsis-associated encephalopathy. Sepsis-related brain damage can drastically reduce a patient's chances of survival. However, a specific treatment for sepsis-associated encephalopathy is not currently available. Consequently, to treat the brain damage caused by sepsis, investigating novel therapeutic strategies is imperative. After establishing the CLP-induced mouse SAE model, we treated the mice with Gyp-XLIX and evaluated apoptosis, neuroinflammation, brain damage, and oxidative stress in the brain tissue of each group of mice. Furthermore, the protective effects of Gyp-XLIX on LPS-treated BV-2 cells were assessed. We discovered that Gyp-XLIX treatment increased the survival rate of CLP-treated mice, alleviated SAE-related cerebral nerve abnormalities, and decreased blood–brain barrier breakdown, all of which could better preserve brain tissue in vivo. Furthermore, we identified associated proteins and found that Gyp-XLIX may reduce oxidative stress, cell apoptosis, and inflammation in the brain tissues of SAE mice. This observation was further validated in vitro. We established that Gyp-XLIX alleviates SAE by targeting PPAR-α. These findings may be important for the clinical applicability of Gyp-XLIX in SAE treatment. We found that Gyp-XLIX can alleviate brain injury in SAE by targeting PPAR-α and is a potential protective agent for SAE.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115027"},"PeriodicalIF":4.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555014","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}
Alzheimer's disease (AD) is a global burden to the healthcare system with no viable treatment options till date. Rodents and primates have been extensively used as models for understanding AD pathogenesis and identifying therapeutic targets. However, the focus is now shifting towards developing alternate models. Zebrafish is emerging as a preferred model for neurodegenerative conditions because of its simple nervous system, highly conserved genome and short duration required to model disease condition. The present study is aimed to develop streptozotocin (STZ)-induced model of sporadic AD (sAD) in zebrafish. STZ was administered to adult zebrafish (4–6 mo) at different doses (1 to 50 mg/kg body weight, intracerebroventricularly). Kaplan-Meier survival analysis revealed time and dose dependent mortality in the zebrafish administered with STZ. Based on survival analysis, 1 to 10 mg/kg body weight of STZ was selected for behavioural, molecular and histological studies. STZ administered fish had anxiety-like and stress behaviour in novel tank and light/dark preference tests. STZ-induced cognitive and memory deficits assessed using novel object recognition and spatial alternation tests. Further, expression of markers of amyloidogenic pathway (appa and bace1) were increased in terms of mRNA and protein levels in a time and dose dependent manner following STZ administration. However, expression of non-amyloidogenic pathway mediator (adam10) was reduced at both mRNA and protein level. Histological assessment using hematoxylin and eosin, and Nissl stain revealed loss of neurons in STZ administered fish. The ratio of phosphor-tauser396/total-tau was increased in STZ administered fish. Based on these findings, 5 mg/kg body weight of STZ was found to be most appropriate dose to exhibit sAD phenotype. Mass spectrometric analysis confirmed the presence of amyloid beta oligomers in brains of STZ administered fish. Transmission electron microscopy also showed the presence of higher order insoluble amyloid fibrils with twists. Immunohistochemical analysis revealed amyloid beta deposits in brain of STZ administered fish. Golgi-cox staining indicated decreased number of dendrites, whereas microglia had increased density, span ratio, soma area and lacunarity. The results of the present study demonstrate presence of AD hallmarks and phenotype in zebrafish 7 days post STZ administration (5 mg/kg). The study validates the potential of STZ-induced sAD in zebrafish as a reliable model for studying pathophysiology and rapid screening of therapeutic molecules against sAD.
{"title":"Zebrafish as a model organism to study sporadic Alzheimer's disease: Behavioural, biochemical and histological validation","authors":"Neha Dhiman , Sonam Deshwal , Vikas Rishi , Nitin Kumar Singhal , Rajat Sandhir","doi":"10.1016/j.expneurol.2024.115034","DOIUrl":"10.1016/j.expneurol.2024.115034","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a global burden to the healthcare system with no viable treatment options till date. Rodents and primates have been extensively used as models for understanding AD pathogenesis and identifying therapeutic targets. However, the focus is now shifting towards developing alternate models. Zebrafish is emerging as a preferred model for neurodegenerative conditions because of its simple nervous system, highly conserved genome and short duration required to model disease condition. The present study is aimed to develop streptozotocin (STZ)-induced model of sporadic AD (sAD) in zebrafish. STZ was administered to adult zebrafish (4–6 mo) at different doses (1 to 50 mg/kg body weight, intracerebroventricularly). Kaplan-Meier survival analysis revealed time and dose dependent mortality in the zebrafish administered with STZ. Based on survival analysis, 1 to 10 mg/kg body weight of STZ was selected for behavioural, molecular and histological studies. STZ administered fish had anxiety-like and stress behaviour in novel tank and light/dark preference tests. STZ-induced cognitive and memory deficits assessed using novel object recognition and spatial alternation tests. Further, expression of markers of amyloidogenic pathway (<em>appa</em> and <em>bace1</em>) were increased in terms of mRNA and protein levels in a time and dose dependent manner following STZ administration. However, expression of non-amyloidogenic pathway mediator (<em>adam10</em>) was reduced at both mRNA and protein level. Histological assessment using hematoxylin and eosin, and Nissl stain revealed loss of neurons in STZ administered fish. The ratio of phosphor-tau<sup>ser396</sup>/total-tau was increased in STZ administered fish. Based on these findings, 5 mg/kg body weight of STZ was found to be most appropriate dose to exhibit sAD phenotype. Mass spectrometric analysis confirmed the presence of amyloid beta oligomers in brains of STZ administered fish. Transmission electron microscopy also showed the presence of higher order insoluble amyloid fibrils with twists. Immunohistochemical analysis revealed amyloid beta deposits in brain of STZ administered fish. Golgi-cox staining indicated decreased number of dendrites, whereas microglia had increased density, span ratio, soma area and lacunarity. The results of the present study demonstrate presence of AD hallmarks and phenotype in zebrafish 7 days post STZ administration (5 mg/kg). The study validates the potential of STZ-induced sAD in zebrafish as a reliable model for studying pathophysiology and rapid screening of therapeutic molecules against sAD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115034"},"PeriodicalIF":4.6,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566900","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 : 2024-10-26DOI: 10.1016/j.expneurol.2024.115033
Jiahong Zhong , Xihui Yu , Yunming Zhong , Liya Tan , Fayou Yang , Jialan Xu , Jianlin Wu , Zhuomiao Lin
Parkinson's disease (PD), a common neurodegenerative disorder characterized by degeneration of the substantia nigra and a marked increase in Lewy bodies in the brain, primarily manifests as motor dysfunction. Glycogen synthase kinase-3 beta (GSK-3β) is known to play a critical role in various pathological processes of neurodegenerative diseases. However, the impact of GSK-3β inhibitors on PD progression and the underlying molecular mechanisms responsible for the effects have not been fully elucidated. Using in vitro and mouse models of 1-methyl-4-phenylpyridine (MPP+)-or methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD, we found that inhibition of GSK-3β activity alleviated mitochondrial damage, cell apoptosis, and neuronal cell loss by promoting the nuclear translocation of transcription factor EB (TFEB), thereby amplifying the autophagy-lysosomal pathway (ALP). Importantly, siRNA silencing of the TFEB gene impaired the GSK-3β inhibitor-mediated activation of the ALP pathway, thus negating the metabolic support required for neuronal functional improvement. Short-term treatment with the GSK-3β inhibitor significantly ameliorated motor dysfunction and improved motor coordination in model mice with MPTP-induced PD. GSK-3β inhibition increased the ALP and TFEB activities in the mice, thereby reducing α-synuclein aggregation and neuronal damage. In conclusion, our study demonstrates that inhibition of GSK-3β activity can delay the pathological processes of PD via promotion of the TFEB–ALP pathway, potentially providing a novel therapeutic target for this neurodegenerative disorder.
帕金森病（Parkinson's disease，PD）是一种常见的神经退行性疾病，以黑质变性和脑内路易体明显增多为特征，主要表现为运动功能障碍。众所周知，糖原合酶激酶-3β（GSK-3β）在神经退行性疾病的各种病理过程中发挥着关键作用。然而，GSK-3β抑制剂对帕金森病进展的影响以及导致这种影响的潜在分子机制尚未完全阐明。我们利用体外和小鼠模型研究了1-甲基-4-苯基吡啶（MPP+）-或甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）-诱导的帕金森病，发现抑制GSK-3β活性可通过促进转录因子EB（TFEB）的核转位，从而扩大自噬-溶酶体途径（ALP），减轻线粒体损伤、细胞凋亡和神经细胞丢失。重要的是，siRNA 沉默 TFEB 基因会损害 GSK-3β 抑制剂介导的 ALP 通路激活，从而抵消神经元功能改善所需的代谢支持。GSK-3β抑制剂的短期治疗显著改善了运动功能障碍，并改善了MPTP诱导的帕金森病模型小鼠的运动协调性。GSK-3β抑制剂可提高小鼠的ALP和TFEB活性，从而减少α-突触核蛋白聚集和神经元损伤。总之，我们的研究表明，抑制GSK-3β的活性可通过促进TFEB-ALP通路延缓帕金森病的病理过程，从而有可能为这种神经退行性疾病提供一种新的治疗靶点。
{"title":"GSK-3β inhibitor amplifies autophagy-lysosomal pathways by regulating TFEB in Parkinson's disease models","authors":"Jiahong Zhong , Xihui Yu , Yunming Zhong , Liya Tan , Fayou Yang , Jialan Xu , Jianlin Wu , Zhuomiao Lin","doi":"10.1016/j.expneurol.2024.115033","DOIUrl":"10.1016/j.expneurol.2024.115033","url":null,"abstract":"<div><div>Parkinson's disease (PD), a common neurodegenerative disorder characterized by degeneration of the substantia nigra and a marked increase in Lewy bodies in the brain, primarily manifests as motor dysfunction. Glycogen synthase kinase-3 beta (GSK-3β) is known to play a critical role in various pathological processes of neurodegenerative diseases. However, the impact of GSK-3β inhibitors on PD progression and the underlying molecular mechanisms responsible for the effects have not been fully elucidated. Using in vitro and mouse models of 1-methyl-4-phenylpyridine (MPP<sup>+</sup>)-or methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD, we found that inhibition of GSK-3β activity alleviated mitochondrial damage, cell apoptosis, and neuronal cell loss by promoting the nuclear translocation of transcription factor EB (TFEB), thereby amplifying the autophagy-lysosomal pathway (ALP). Importantly, siRNA silencing of the TFEB gene impaired the GSK-3β inhibitor-mediated activation of the ALP pathway, thus negating the metabolic support required for neuronal functional improvement. Short-term treatment with the GSK-3β inhibitor significantly ameliorated motor dysfunction and improved motor coordination in model mice with MPTP-induced PD. GSK-3β inhibition increased the ALP and TFEB activities in the mice, thereby reducing α-synuclein aggregation and neuronal damage. In conclusion, our study demonstrates that inhibition of GSK-3β activity can delay the pathological processes of PD via promotion of the TFEB–ALP pathway, potentially providing a novel therapeutic target for this neurodegenerative disorder.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115033"},"PeriodicalIF":4.6,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566807","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 : 2024-10-25DOI: 10.1016/j.expneurol.2024.115031
Yujing Zhao , Hongyan Guo , Qiao Li , Nan Wang , Chaoying Yan , Simei Zhang , Yicong Dong , Chang Liu , Wei Gao , Yaomin Zhu , Qing Li
Ferroptosis is involved in neurodegenerative disorders including diabetes-associated cognitive impairment (DACI). As central immune cells, microglia have strong siderophilic properties. However, the role of iron deposition in microglia and the underlying regulatory mechanism remains unclear in DACI. Here, we established high glucose (HG) model in BV2/HMC3 cells and diabetes model in C57BL/6 J mice with HFD and STZ. Transmission Electron Microscopy, Western blot, assay kits of Fe2+, GSH/GSSG, MDA and ROS were carried out in vitro. Prussian blue staining, Western blot and immunofluorescence were implemented in vivo. Y-maze and novel object recognition were performed to assess cognitive performance. LP17 was used to inhibit TREM1 (triggering receptor expressed on myeloid cells 1) specifically in vivo and vitro. We found excessively deposited iron and significant reduction in antioxidants in hippocampal microglia of mice with DACI, concomitant with increased TREM1 (a microglia-specific inflammatory amplifier). Furthermore, LP17 (TREM1 specific inhibitor) ameliorated cognitive impairment caused by HFD/STZ through relieving iron accumulation and antioxidant inactivation. In vitro, ferroptosis was induced by HG in mice microglia-BV2 and human microglia-HMC3 cells, which could be blocked by a ferroptosis inhibitor-Fer-1 and LP17. Moreover, PERK pathway of endoplasmic reticulum stress was activated by HG, and then reversed by PERK inhibitor GSK2606414 and LP17 followed by improved ferroptosis in HG-cultured BV2. In summary, our results indicated that TREM1 effectively aggravates T2DM-associated microglial iron accumulation through the PERK pathway of ERS, which contributes to antioxidant inactivation and lipid peroxidation, eventually, massively boosted ROS result in microglial ferroptosis. The mechanism elucidation in our study may shed light on targeted therapy of DACI.
{"title":"TREM1 induces microglial ferroptosis through the PERK pathway in diabetic-associated cognitive impairment","authors":"Yujing Zhao , Hongyan Guo , Qiao Li , Nan Wang , Chaoying Yan , Simei Zhang , Yicong Dong , Chang Liu , Wei Gao , Yaomin Zhu , Qing Li","doi":"10.1016/j.expneurol.2024.115031","DOIUrl":"10.1016/j.expneurol.2024.115031","url":null,"abstract":"<div><div>Ferroptosis is involved in neurodegenerative disorders including diabetes-associated cognitive impairment (DACI). As central immune cells, microglia have strong siderophilic properties. However, the role of iron deposition in microglia and the underlying regulatory mechanism remains unclear in DACI. Here, we established high glucose (HG) model in BV2/HMC3 cells and diabetes model in C57BL/6 J mice with HFD and STZ. Transmission Electron Microscopy, Western blot, assay kits of Fe<sup>2+</sup>, GSH/GSSG, MDA and ROS were carried out <em>in vitro</em>. Prussian blue staining, Western blot and immunofluorescence were implemented <em>in vivo</em>. Y-maze and novel object recognition were performed to assess cognitive performance. LP17 was used to inhibit TREM1 (triggering receptor expressed on myeloid cells 1) specifically <em>in vivo and vitro</em>. We found excessively deposited iron and significant reduction in antioxidants in hippocampal microglia of mice with DACI, concomitant with increased TREM1 (a microglia-specific inflammatory amplifier). Furthermore, LP17 (TREM1 specific inhibitor) ameliorated cognitive impairment caused by HFD/STZ through relieving iron accumulation and antioxidant inactivation. <em>In vitro</em>, ferroptosis was induced by HG in mice microglia-BV2 and human microglia-HMC3 cells, which could be blocked by a ferroptosis inhibitor-Fer-1 and LP17. Moreover, PERK pathway of endoplasmic reticulum stress was activated by HG, and then reversed by PERK inhibitor GSK2606414 and LP17 followed by improved ferroptosis in HG-cultured BV2. In summary, our results indicated that TREM1 effectively aggravates T2DM-associated microglial iron accumulation through the PERK pathway of ERS, which contributes to antioxidant inactivation and lipid peroxidation, eventually, massively boosted ROS result in microglial ferroptosis. The mechanism elucidation in our study may shed light on targeted therapy of DACI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115031"},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497765","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 : 2024-10-25DOI: 10.1016/j.expneurol.2024.115029
Mengqing Li , Yaxian Mo , Qinyao Yu , Umer Anayyat , Hua Yang , Fen Zhang , Yunpeng Wei , Xiaomei Wang
Alzheimer's disease (AD) is a geriatric disorder that can be roughly classified into sporadic AD and hereditary AD. The latter is strongly associated with genetic factors, and its treatment poses greater challenges compared to sporadic AD. Rotating magnetic fields (RMF) is a non-invasive treatment known to have diverse biological effects, including the modulation of the central nervous system and aging. However, the impact of RMF on hereditary AD and its underlying mechanism remain unexplored. In this study, we exposed APP/PS1 mice to RMF (2 h/day, 0.2 T, 4 Hz) for a duration of 6 months. The results demonstrated that RMF treatment significantly ameliorated their cognitive and memory impairments, attenuated neuronal damage, and reduced amyloid deposition. Furthermore, RNA-sequencing analysis revealed a significant enrichment of autophagy-related genes and the PI3K/AKT-mTOR signaling pathway. Western blotting further confirmed that RMF activated autophagy and suppressed the phosphorylation of proteins associated with the PI3K/AKT/mTOR signaling pathway in APP/PS1 mice. These protective effects and the underlying mechanism were also observed in Aβ25–35-exposed HT22 cells. Collectively, our findings indicate that RMF improves cognitive and memory dysfunction in APP/PS1 mice by activating autophagy and inhibiting the PI3K/AKT/mTOR signaling pathway, thus highlighting the potential of RMF as a clinical treatment for hereditary AD.
{"title":"Rotating magnetic field improves cognitive and memory impairments in APP/PS1 mice by activating autophagy and inhibiting the PI3K/AKT/mTOR signaling pathway","authors":"Mengqing Li , Yaxian Mo , Qinyao Yu , Umer Anayyat , Hua Yang , Fen Zhang , Yunpeng Wei , Xiaomei Wang","doi":"10.1016/j.expneurol.2024.115029","DOIUrl":"10.1016/j.expneurol.2024.115029","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a geriatric disorder that can be roughly classified into sporadic AD and hereditary AD. The latter is strongly associated with genetic factors, and its treatment poses greater challenges compared to sporadic AD. Rotating magnetic fields (RMF) is a non-invasive treatment known to have diverse biological effects, including the modulation of the central nervous system and aging. However, the impact of RMF on hereditary AD and its underlying mechanism remain unexplored. In this study, we exposed APP/PS1 mice to RMF (2 h/day, 0.2 T, 4 Hz) for a duration of 6 months. The results demonstrated that RMF treatment significantly ameliorated their cognitive and memory impairments, attenuated neuronal damage, and reduced amyloid deposition. Furthermore, RNA-sequencing analysis revealed a significant enrichment of autophagy-related genes and the PI3K/AKT-mTOR signaling pathway. Western blotting further confirmed that RMF activated autophagy and suppressed the phosphorylation of proteins associated with the PI3K/AKT/mTOR signaling pathway in APP/PS1 mice. These protective effects and the underlying mechanism were also observed in Aβ<sub>25</sub><sub>–</sub><sub>35</sub>-exposed HT22 cells. Collectively, our findings indicate that RMF improves cognitive and memory dysfunction in APP/PS1 mice by activating autophagy and inhibiting the PI3K/AKT/mTOR signaling pathway, thus highlighting the potential of RMF as a clinical treatment for hereditary AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115029"},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497763","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 : 2024-10-25DOI: 10.1016/j.expneurol.2024.115030
Weiguo Li , Alice A. Li , Xingju Nie , Joshua Voltin , Lianying He , Eda Karakaya , Jazlyn Edwards , Sarah Jamil , Kareem Abdelsaid , Maria Fatima Falangola , Adviye Ergul
Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID.
糖尿病是所有类型痴呆症的主要风险因素。其根本原因尚不完全清楚，也缺乏预防性治疗策略。此前，我们已经证明，在微栓子（ME）认知障碍& 痴呆（VCID）的血管作用模型中，糖尿病大鼠而非对照组大鼠会出现进行性认知功能下降。鉴于脑血管功能障碍是糖尿病和 VCID 之间的共同病理变化，我们假设可以通过改善糖尿病大鼠的内皮功能来预防 ME 模型中的认知功能障碍。我们的治疗范式基于 LACI-2 试验，该试验评估了单硝酸异山梨酯（ISMN）和西洛他唑（Cil）治疗小血管疾病进展的疗效。对照组和糖尿病大鼠接受 ISMN/Cil 或药物治疗 4 周，然后注射胆固醇晶体 ME 并监测行为结果。通过弥散核磁共振成像评估大脑微观结构的完整性。血浆生物标志物采用 MarkVCID 联盟推荐的血管生成、神经学和淀粉样β 42/40 面板进行评估。在本研究中，接受治疗的动物没有出现之前在未经治疗的糖尿病大鼠身上观察到的行为障碍和组织完整性丧失。治疗改善了组织灌注，但血浆生物标志物并无差异。这些结果表明，在注射ME前用ISMN/Cil恢复内皮功能可通过改善内皮完整性来防止ME对糖尿病大鼠可能产生的有害影响，是一种实用的VCID预防和治疗策略。
{"title":"Combination treatment with cilostazol and isosorbide mononitrate attenuates microemboli-mediated vascular cognitive impairment and improves imaging and plasma biomarkers in diabetic rats","authors":"Weiguo Li , Alice A. Li , Xingju Nie , Joshua Voltin , Lianying He , Eda Karakaya , Jazlyn Edwards , Sarah Jamil , Kareem Abdelsaid , Maria Fatima Falangola , Adviye Ergul","doi":"10.1016/j.expneurol.2024.115030","DOIUrl":"10.1016/j.expneurol.2024.115030","url":null,"abstract":"<div><div>Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115030"},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554999","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 : 2024-10-24DOI: 10.1016/j.expneurol.2024.115021
Fangxue Zheng , Taiwei Dong , Yi Chen , Lang Wang , Guoping Peng
Border-associated macrophages (BAMs) constitute a highly heterogeneous group of central nervous system-resident macrophages at the brain boundaries. Despite their significance, BAMs have mainly been overlooked compared to microglia, resulting in a limited understanding of their functions. However, recent advancements in single-cell immunophenotyping and transcriptomic analyses of BAMs have revealed a previously unrecognized complexity in these cells, in addition to their critical roles under non-pathological conditions and diseases like Alzheimer's disease (AD), Parkinson's disease, glioma, and ischemic stroke. In this review, we discuss the origins, self-renewal capabilities, and extensive heterogeneity of BAMs, and clarify their important physiological functions such as immune monitoring, waste removal and vascular permeability regulation. We also summarize experimental evidence linking BAMs to the progression of AD. Finally, we review therapeutic strategies targeting brain innate immune cells mainly focusing on strategies aimed at modulating BAMs to treat AD and evaluate their potential in clinical applications.
边界相关巨噬细胞（BAMs）是大脑边界中枢神经系统驻留巨噬细胞的一个高度异质性群体。尽管边界相关巨噬细胞意义重大，但与小胶质细胞相比，它们主要被忽视，导致人们对其功能的了解有限。然而，最近在单细胞免疫分型和 BAMs 转录组学分析方面取得的进展揭示了这些细胞以前未曾认识到的复杂性，以及它们在非病理状态和疾病（如阿尔茨海默病（AD）、帕金森病、胶质瘤和缺血性中风）中的关键作用。在这篇综述中，我们讨论了 BAMs 的起源、自我更新能力和广泛的异质性，并阐明了它们的重要生理功能，如免疫监测、废物清除和血管通透性调节。我们还总结了将 BAMs 与 AD 进展联系起来的实验证据。最后，我们回顾了针对脑先天性免疫细胞的治疗策略，主要侧重于旨在调节 BAMs 以治疗 AD 的策略，并评估其在临床应用中的潜力。
{"title":"Border-associated macrophages: From physiology to therapeutic targets in Alzheimer's disease","authors":"Fangxue Zheng , Taiwei Dong , Yi Chen , Lang Wang , Guoping Peng","doi":"10.1016/j.expneurol.2024.115021","DOIUrl":"10.1016/j.expneurol.2024.115021","url":null,"abstract":"<div><div>Border-associated macrophages (BAMs) constitute a highly heterogeneous group of central nervous system-resident macrophages at the brain boundaries. Despite their significance, BAMs have mainly been overlooked compared to microglia, resulting in a limited understanding of their functions. However, recent advancements in single-cell immunophenotyping and transcriptomic analyses of BAMs have revealed a previously unrecognized complexity in these cells, in addition to their critical roles under non-pathological conditions and diseases like Alzheimer's disease (AD), Parkinson's disease, glioma, and ischemic stroke. In this review, we discuss the origins, self-renewal capabilities, and extensive heterogeneity of BAMs, and clarify their important physiological functions such as immune monitoring, waste removal and vascular permeability regulation. We also summarize experimental evidence linking BAMs to the progression of AD. Finally, we review therapeutic strategies targeting brain innate immune cells mainly focusing on strategies aimed at modulating BAMs to treat AD and evaluate their potential in clinical applications.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115021"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497760","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 : 2024-10-24DOI: 10.1016/j.expneurol.2024.115026
Sweta Priyadarshini Pradhan , Anindita Behera , Pratap Kumar Sahu
Oxidative stress is one of the major causes of different metabolic disorders, including diabetes, cardiovascular diseases, neurodegenerative diseases and cancers. Some metabolic disorders like diabetes mellitus leads to secondary complications after micro and macrovascular complications. Some of the most prevalent neurodegenerative diseases, like cognitive impairment and Alzheimer's disease, are found in chronic diabetic patients. The present study is designed to understand the mechanism of interconnection between diabetes mellitus and cognitive deficit using the alloxan model of diabetes-induced cognitive deficit in the rat model. The alloxan monohydrate produces reactive oxygen species, producing superoxide free radicals, hydrogen peroxide and hydroxyl radicals. The hydroxyl radicals ultimately cause the death of beta cells, causing diabetes. Hence, the correlation of oxidative stress and neurodegeneration in cognitive impairment is the trigger for this study. In the present study, we investigate the ameliorative effect of vildagliptin (VLD) and its conjugated nanoparticles against alloxan-associated brain damage due to oxidative stress. The gold (Au), selenium (Se) nanoparticles, and bimetallic (Se@Au) nanocomposites of VLD are synthesized and assessed for improvement in their brain availability. The in-vitro antioxidant evaluation of the VLD and nanoparticles is done using DPPH, ABTS, and FRAP assay. The memory-related neurobehavioral studies, in-vivo antioxidant studies, in-vivo biochemical studies, and histopathological examinations are evaluated in rat brains. The VLD and its nanoformulations exhibited in-vitro and in-vivo antioxidant properties significantly (p < 0.01). They reduced the activity of AChE and nitrite in the alloxan diabetic rats. The bimetallic Se@Au VLDNCs displayed a more protective effect than VLD, VLD–AuNPs, and VLD–SeNPs.
{"title":"Effect of vildagliptin conjugated monometallic nanoparticles and bimetallic nanocomposites on diabetes-induced cognitive deficit","authors":"Sweta Priyadarshini Pradhan , Anindita Behera , Pratap Kumar Sahu","doi":"10.1016/j.expneurol.2024.115026","DOIUrl":"10.1016/j.expneurol.2024.115026","url":null,"abstract":"<div><div>Oxidative stress is one of the major causes of different metabolic disorders, including diabetes, cardiovascular diseases, neurodegenerative diseases and cancers. Some metabolic disorders like diabetes mellitus leads to secondary complications after micro and macrovascular complications. Some of the most prevalent neurodegenerative diseases, like cognitive impairment and Alzheimer's disease, are found in chronic diabetic patients. The present study is designed to understand the mechanism of interconnection between diabetes mellitus and cognitive deficit using the alloxan model of diabetes-induced cognitive deficit in the rat model. The alloxan monohydrate produces reactive oxygen species, producing superoxide free radicals, hydrogen peroxide and hydroxyl radicals. The hydroxyl radicals ultimately cause the death of beta cells, causing diabetes. Hence, the correlation of oxidative stress and neurodegeneration in cognitive impairment is the trigger for this study. In the present study, we investigate the ameliorative effect of vildagliptin (VLD) and its conjugated nanoparticles against alloxan-associated brain damage due to oxidative stress. The gold (Au), selenium (Se) nanoparticles, and bimetallic (Se@Au) nanocomposites of VLD are synthesized and assessed for improvement in their brain availability. The in-vitro antioxidant evaluation of the VLD and nanoparticles is done using DPPH, ABTS, and FRAP assay. The memory-related neurobehavioral studies, in-vivo antioxidant studies, in-vivo biochemical studies, and histopathological examinations are evaluated in rat brains. The VLD and its nanoformulations exhibited in-vitro and in-vivo antioxidant properties significantly (<em>p</em> < 0.01). They reduced the activity of AChE and nitrite in the alloxan diabetic rats. The bimetallic Se@Au VLDNCs displayed a more protective effect than VLD, VLD–AuNPs, and VLD–SeNPs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115026"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497761","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}
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