Pub Date : 2024-11-22DOI: 10.1016/j.mcn.2024.103980
Zehua Tan , Ruixin Xia , Xin Zhao , Zile Yang, Haiying Liu, Wenting Wang
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication deficits, as well as restricted or repetitive behaviors or interests. Although the etiology of ASD remains unclear, there is abundant evidence suggesting that microglial dysfunction is likely to be a significant factor in the pathophysiology of ASD. Microglia, the primary innate immune cells in the central nervous system (CNS), play a crucial role in brain development and homeostasis. Recently, numerous studies have shown that microglia in ASD models display various abnormalities including morphology, function, cellular interactions, genetic and epigenetic factors, as well as the expression of receptors, transcription factors, and cytokines. They impact normal neural development through various mechanisms contributing to ASD, such as neuroinflammation, and alterations in synaptic formation and pruning. The focus of this review is on recent studies regarding microglial abnormalities in ASD and their effects on the onset and progression of ASD at both cellular and molecular levels. It can provide insight into the specific contribution of microglia to ASD pathogenesis and help in designing potential therapeutic and preventative strategies targeting microglia.
{"title":"Potential key pathophysiological participant and treatment target in autism spectrum disorder: Microglia","authors":"Zehua Tan , Ruixin Xia , Xin Zhao , Zile Yang, Haiying Liu, Wenting Wang","doi":"10.1016/j.mcn.2024.103980","DOIUrl":"10.1016/j.mcn.2024.103980","url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication deficits, as well as restricted or repetitive behaviors or interests. Although the etiology of ASD remains unclear, there is abundant evidence suggesting that microglial dysfunction is likely to be a significant factor in the pathophysiology of ASD. Microglia, the primary innate immune cells in the central nervous system (CNS), play a crucial role in brain development and homeostasis. Recently, numerous studies have shown that microglia in ASD models display various abnormalities including morphology, function, cellular interactions, genetic and epigenetic factors, as well as the expression of receptors, transcription factors, and cytokines. They impact normal neural development through various mechanisms contributing to ASD, such as neuroinflammation, and alterations in synaptic formation and pruning. The focus of this review is on recent studies regarding microglial abnormalities in ASD and their effects on the onset and progression of ASD at both cellular and molecular levels. It can provide insight into the specific contribution of microglia to ASD pathogenesis and help in designing potential therapeutic and preventative strategies targeting microglia.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103980"},"PeriodicalIF":2.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1016/j.mcn.2024.103979
Dengpan Song , Mengyuan Li , Longxiao Zhang , Kaiyuan Zhang , Yuan An , Mengzhao Feng , Fang Wang , Chi-Tai Yeh , Jian Wang , Fuyou Guo
Background
Intracerebral hemorrhage (ICH) has a high incidence and mortality rate among cerebrovascular diseases, and effective treatments are lacking. Sphingosine-1-phosphate receptor 3 (S1PR3) is associated with secondary immune inflammatory injury following ICH. However, its relationship with neuronal apoptosis and the specific underlying mechanism are not clear.
Methods
We observed the effect of S1PR3 on neuronal apoptosis by assessing neurobehavioral scores, performing Western blot (WB) analysis, and performing TUNEL staining in a mouse model of ICH. Moreover, WBs and flow cytometry were used to study the specific mechanism and signaling pathways in HT22 cells in vitro.
Results
The expression of S1PR3, CCL2, TNF-α, and cleaved-caspase-3 (c-caspase-3) and neuronal apoptosis were significantly increased after ICH, accompanied by neurobehavioral deterioration. These effects were significantly improved by treatment with CAY10444, a specific S1PR3 antagonist. After S1P stimulation of HT22 cells, the expression of S1PR3, CCL2, TNF-α and c-caspase-3 increased, and neuronal apoptosis increased by activating caspase-3 through the downstream PI3K/AKT apoptosis signaling pathway. After CAY10444 treatment, the expression of CCL2, TNF-α and c-caspase-3 was significantly reduced, and the PI3K/AKT apoptotic signaling pathway was regulated to reduce neuronal apoptosis.
Conclusion
An increase in S1P/S1PR3 after ICH may induce neuronal apoptosis by increasing TNF-α expression and activating the PI3K/AKT signaling pathway and the expression of caspase-3 effector proteins. CAY10444 can reduce neuronal apoptosis, improve symptoms and play a neuroprotective role by antagonizing S1PR3. S1PR3 may be a promising therapeutic target.
背景在脑血管疾病中，脑出血（ICH）的发病率和死亡率都很高，而且缺乏有效的治疗方法。两性鞘氨醇-1-磷酸受体 3（S1PR3）与 ICH 后的继发性免疫炎症损伤有关。我们在 ICH 小鼠模型中通过神经行为评分、Western 印迹（WB）分析和 TUNEL 染色观察了 S1PR3 对神经细胞凋亡的影响。结果 ICH后S1PR3、CCL2、TNF-α和裂解-caspase-3（c-caspase-3）的表达和神经元凋亡显著增加，并伴随神经行为的恶化。使用特异性 S1PR3 拮抗剂 CAY10444 治疗可明显改善这些影响。S1P刺激HT22细胞后，S1PR3、CCL2、TNF-α和c-caspase-3的表达增加，通过下游的PI3K/AKT凋亡信号通路激活caspase-3，从而增加神经元凋亡。CAY10444治疗后，CCL2、TNF-α和c-caspase-3的表达明显减少，PI3K/AKT凋亡信号通路被调控，从而减少神经元凋亡。CAY10444 可通过拮抗 S1PR3 减少神经元凋亡，改善症状，发挥神经保护作用。S1PR3 可能是一个很有前景的治疗靶点。
{"title":"Sphingosine-1-phosphate receptor 3 promotes neuronal apoptosis via the TNF-α/caspase-3 signaling pathway after acute intracerebral hemorrhage","authors":"Dengpan Song , Mengyuan Li , Longxiao Zhang , Kaiyuan Zhang , Yuan An , Mengzhao Feng , Fang Wang , Chi-Tai Yeh , Jian Wang , Fuyou Guo","doi":"10.1016/j.mcn.2024.103979","DOIUrl":"10.1016/j.mcn.2024.103979","url":null,"abstract":"<div><h3>Background</h3><div>Intracerebral hemorrhage (ICH) has a high incidence and mortality rate among cerebrovascular diseases, and effective treatments are lacking. Sphingosine-1-phosphate receptor 3 (S1PR3) is associated with secondary immune inflammatory injury following ICH. However, its relationship with neuronal apoptosis and the specific underlying mechanism are not clear.</div></div><div><h3>Methods</h3><div>We observed the effect of S1PR3 on neuronal apoptosis by assessing neurobehavioral scores, performing Western blot (WB) analysis, and performing TUNEL staining in a mouse model of ICH. Moreover, WBs and flow cytometry were used to study the specific mechanism and signaling pathways in HT22 cells in vitro.</div></div><div><h3>Results</h3><div>The expression of S1PR3, CCL2, TNF-α, and cleaved-caspase-3 (c-caspase-3) and neuronal apoptosis were significantly increased after ICH, accompanied by neurobehavioral deterioration. These effects were significantly improved by treatment with CAY10444, a specific S1PR3 antagonist. After S1P stimulation of HT22 cells, the expression of S1PR3, CCL2, TNF-α and c-caspase-3 increased, and neuronal apoptosis increased by activating caspase-3 through the downstream PI3K/AKT apoptosis signaling pathway. After CAY10444 treatment, the expression of CCL2, TNF-α and c-caspase-3 was significantly reduced, and the PI3K/AKT apoptotic signaling pathway was regulated to reduce neuronal apoptosis.</div></div><div><h3>Conclusion</h3><div>An increase in S1P/S1PR3 after ICH may induce neuronal apoptosis by increasing TNF-α expression and activating the PI3K/AKT signaling pathway and the expression of caspase-3 effector proteins. CAY10444 can reduce neuronal apoptosis, improve symptoms and play a neuroprotective role by antagonizing S1PR3. S1PR3 may be a promising therapeutic target.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103979"},"PeriodicalIF":2.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.mcn.2024.103976
Mikaela M Ceder, Kajsa A Magnusson, Hannah M Weman, Katharina Henriksson, Linn Andréasson, Teresa Lindström, Oskar Wiggins, Malin C Lagerström
Glycine receptors are ligand-gated chloride-selective channels that control excitability in the central nervous system (CNS). Herein, we have investigated the mRNA expression of the glycine receptor alpha 1 (Glra1), alpha 2 (Glra2), alpha 4 (Glra4) and beta (Glrb) subunits, in adult female and male mice. Single-cell RNA sequencing data re-analysis of the Zeisel et al. (2018) dataset indicated widespread expression of Glra1, Glra2 and Glrb in the CNS, while only a few cells in the cortex, striatum, thalamus, midbrain and spinal cord expressed Glra4. Highest occurrence of Glra1, Glra2 and Glrb were found in the brainstem. Moreover, Glra1 and Glrb were revealed to have the highest occurrences in the spinal cord of the investigated subunits. However, both Glra2 and Glrb had a more widespread expression in the CNS compared with Glra1 and Glra4. Bulk quantitative real-time-PCR (qRT-PCR) analysis revealed Glra1 expression in the hypothalamus, thalamus, brainstem and the spinal cord, and widespread, but low, Glra2 and Glrb expression in the CNS. Moreover, Glrb could be detected in a few visceral organs. Additionally, females and males were found to express Glra1, Glra2 and Glrb differently in certain brain areas such as the brainstem. Expression levels of Glra4 were too low to be detected using qRT-PCR. Lastly, RNAscope spatially validated the expression of Glra1, Glra2 and Glrb in the areas indicated by the single-cell and bulk analyses, and further revealed that Glra4 can be detected in the cortex, amygdala, hypothalamus, thalamus, brainstem, especially the cochlear nucleus, and in the spinal cord.
{"title":"The mRNA expression profile of glycine receptor subunits alpha 1, alpha 2, alpha 4 and beta in female and male mice.","authors":"Mikaela M Ceder, Kajsa A Magnusson, Hannah M Weman, Katharina Henriksson, Linn Andréasson, Teresa Lindström, Oskar Wiggins, Malin C Lagerström","doi":"10.1016/j.mcn.2024.103976","DOIUrl":"https://doi.org/10.1016/j.mcn.2024.103976","url":null,"abstract":"<p><p>Glycine receptors are ligand-gated chloride-selective channels that control excitability in the central nervous system (CNS). Herein, we have investigated the mRNA expression of the glycine receptor alpha 1 (Glra1), alpha 2 (Glra2), alpha 4 (Glra4) and beta (Glrb) subunits, in adult female and male mice. Single-cell RNA sequencing data re-analysis of the Zeisel et al. (2018) dataset indicated widespread expression of Glra1, Glra2 and Glrb in the CNS, while only a few cells in the cortex, striatum, thalamus, midbrain and spinal cord expressed Glra4. Highest occurrence of Glra1, Glra2 and Glrb were found in the brainstem. Moreover, Glra1 and Glrb were revealed to have the highest occurrences in the spinal cord of the investigated subunits. However, both Glra2 and Glrb had a more widespread expression in the CNS compared with Glra1 and Glra4. Bulk quantitative real-time-PCR (qRT-PCR) analysis revealed Glra1 expression in the hypothalamus, thalamus, brainstem and the spinal cord, and widespread, but low, Glra2 and Glrb expression in the CNS. Moreover, Glrb could be detected in a few visceral organs. Additionally, females and males were found to express Glra1, Glra2 and Glrb differently in certain brain areas such as the brainstem. Expression levels of Glra4 were too low to be detected using qRT-PCR. Lastly, RNAscope spatially validated the expression of Glra1, Glra2 and Glrb in the areas indicated by the single-cell and bulk analyses, and further revealed that Glra4 can be detected in the cortex, amygdala, hypothalamus, thalamus, brainstem, especially the cochlear nucleus, and in the spinal cord.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"103976"},"PeriodicalIF":2.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.mcn.2024.103978
Hyun Jung Kwon , Hyo Young Jung , Soo Young Choi , In Koo Hwang , Dae Won Kim , Min Jea Shin
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.
{"title":"TAT-PPA1 protects against oxidative stress-induced loss of dopaminergic neurons","authors":"Hyun Jung Kwon , Hyo Young Jung , Soo Young Choi , In Koo Hwang , Dae Won Kim , Min Jea Shin","doi":"10.1016/j.mcn.2024.103978","DOIUrl":"10.1016/j.mcn.2024.103978","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain, resulting in severe motor impairments. Inorganic pyrophosphatase 1 (PPA1) plays a key role in various biological processes, and this study introduces a cell-penetrating PPA1 fusion protein (TAT-PPA1) to explore its transduction into cells and brain tissues. TAT-PPA1 effectively penetrates SH-SY5Y cells and the SN region of PD animal models without toxicity, exhibiting protective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-)-induced cell death. TAT-PPA1 revealed an inhibitory influence on the MAPK signaling pathway and MPTP-induced reactive oxygen species (ROS) production. TAT-PPA1 suppresses JNK, AKT, p53, ERK, and p38 phosphorylation, showcasing its multifaceted role in cell survival pathways. In the MPTP-induced PD animal model, TAT-PPA1 prevents dopaminergic cell death and enhances motor function. This study shows that TAT-PPA1 protects against oxidative stress and cell death in neurodegenerative diseases, suggesting potential as a PD treatment.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103978"},"PeriodicalIF":2.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-20DOI: 10.1016/j.mcn.2024.103977
Mustafa C. Beker , Mehmet O. Altintas , Enes Dogan , Cigdem Bayraktaroglu , Buse Balaban , Aysenur Ozpinar , Nursena Sengun , Serdar Altunay , Ertugrul Kilic
Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.
{"title":"Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury","authors":"Mustafa C. Beker , Mehmet O. Altintas , Enes Dogan , Cigdem Bayraktaroglu , Buse Balaban , Aysenur Ozpinar , Nursena Sengun , Serdar Altunay , Ertugrul Kilic","doi":"10.1016/j.mcn.2024.103977","DOIUrl":"10.1016/j.mcn.2024.103977","url":null,"abstract":"<div><div>Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103977"},"PeriodicalIF":2.6,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1016/j.mcn.2024.103974
Nina Daniels, Aidan D. Bindoff, James C. Vickers, Anna E. King , Jessica M. Collins
Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.
{"title":"Vulnerability of neurofilament-expressing neurons in frontotemporal dementia","authors":"Nina Daniels, Aidan D. Bindoff, James C. Vickers, Anna E. King , Jessica M. Collins","doi":"10.1016/j.mcn.2024.103974","DOIUrl":"10.1016/j.mcn.2024.103974","url":null,"abstract":"<div><div>Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103974"},"PeriodicalIF":2.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1016/j.mcn.2024.103975
Fotis Andromidas , Brooke E. Mackinnon , Abigail J. Myers , Melanie M. Shaffer , Ayat Brahimi , Saeid Atashpanjeh , Tiana L. Vazquez , Timmy Le , Evan R. Jellison , Susan Staurovsky , Andrew O. Koob
Astrocytes are tasked with regulating the synaptic environment. Early stages of various neurodegenerative diseases are characterized by synapse loss, and astrocytic atrophy and dysfunction has been proposed as a possible cause. α-Synuclein (αS) is a highly expressed neuronal protein located in the synapse that can be released in the extracellular space. Evidence points to astrocytes as being responsible for uptake and degradation of extracellular αS. Therefore, misfolded active fibrillized αS resulting in protein inclusions and aggregates could be due to astrocytic dysfunction. Despite these pathological hallmarks and lines of evidence, the autophagic function of astrocytes in response to monomeric non-active αS to model healthy conditions has not been investigated. Human primary cortical astrocytes were treated with 100 nM of extracellular monomeric non-active αS alone, and in combination with N-terminal binding monomeric γ-synuclein (γS) as a control. Western blot analysis and super resolution imaging of HiLyte-488 labeled αS confirmed successful internalization of αS at 12, 24 and 48 h after treatment, while αS dimers were only observed at 48 h. Western blot analysis also confirmed αS's ability to induce autophagic flux by 48 h. Annexin V/PI flow cytometry results revealed increased early apoptosis at 24 h, but which resolved itself by 48 h, indicating no cell death in cortical astrocytes at all time points, suggesting astrocytes can manage the protein degradation demand of monomeric αS in healthy physiological conditions. Likewise, astrocytes reduced secretion of apolipoprotein (ApoE), a protein involved in pro-inflammatory pathways, synapse regulation, and autophagy by 12 h. Similarly, total c-JUN protein levels, a transcription factor involved in pro-inflammatory pathways increased by 12 h in the nuclear fraction. Therefore, astrocytes are able to respond and degrade αS in healthy physiological conditions, and astrocyte dysfunction could precede detrimental αS accumulation.
{"title":"Astrocytes initiate autophagic flux and maintain cell viability after internalizing non-active native extracellular α-synuclein","authors":"Fotis Andromidas , Brooke E. Mackinnon , Abigail J. Myers , Melanie M. Shaffer , Ayat Brahimi , Saeid Atashpanjeh , Tiana L. Vazquez , Timmy Le , Evan R. Jellison , Susan Staurovsky , Andrew O. Koob","doi":"10.1016/j.mcn.2024.103975","DOIUrl":"10.1016/j.mcn.2024.103975","url":null,"abstract":"<div><div>Astrocytes are tasked with regulating the synaptic environment. Early stages of various neurodegenerative diseases are characterized by synapse loss, and astrocytic atrophy and dysfunction has been proposed as a possible cause. α-Synuclein (αS) is a highly expressed neuronal protein located in the synapse that can be released in the extracellular space. Evidence points to astrocytes as being responsible for uptake and degradation of extracellular αS. Therefore, misfolded active fibrillized αS resulting in protein inclusions and aggregates could be due to astrocytic dysfunction. Despite these pathological hallmarks and lines of evidence, the autophagic function of astrocytes in response to monomeric non-active αS to model healthy conditions has not been investigated. Human primary cortical astrocytes were treated with 100 nM of extracellular monomeric non-active αS alone, and in combination with N-terminal binding monomeric γ-synuclein (γS) as a control. Western blot analysis and super resolution imaging of HiLyte-488 labeled αS confirmed successful internalization of αS at 12, 24 and 48 h after treatment, while αS dimers were only observed at 48 h. Western blot analysis also confirmed αS's ability to induce autophagic flux by 48 h. Annexin V/PI flow cytometry results revealed increased early apoptosis at 24 h, but which resolved itself by 48 h, indicating no cell death in cortical astrocytes at all time points, suggesting astrocytes can manage the protein degradation demand of monomeric αS in healthy physiological conditions. Likewise, astrocytes reduced secretion of apolipoprotein (ApoE), a protein involved in pro-inflammatory pathways, synapse regulation, and autophagy by 12 h. Similarly, total c-JUN protein levels, a transcription factor involved in pro-inflammatory pathways increased by 12 h in the nuclear fraction. Therefore, astrocytes are able to respond and degrade αS in healthy physiological conditions, and astrocyte dysfunction could precede detrimental αS accumulation.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103975"},"PeriodicalIF":2.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1016/j.mcn.2024.103972
Anjit K. Harijan , Retnamony Kalaiarasan , Amit Kumar Ghosh , Ruchi P. Jain , Amal Kanti Bera
Gut microbe-derived short-chain fatty acids (SCFAs) are known to have a profound impact on various brain functions, including cognition, mood, and overall neurological health. However, their role, if any, in protecting against hypoxic injury and ischemic stroke has not been extensively studied. In this study, we investigated the effects of two major SCFAs abundant in the gut, propionate (P) and butyrate (B), on hypoxia-reperfusion injury using a neuronal cell line and a zebrafish model. Neuro 2a (N2a) cells treated with P and B exhibited reduced levels of mitochondrial and cytosolic reactive oxygen species (ROS), diminished loss of mitochondrial membrane potential, suppressed caspase activation, and lower rates of cell death when exposed to CoCl2, a chemical commonly used to simulate hypoxia. Furthermore, adult zebrafish fed SCFA-supplemented feeds showed less susceptibility to hypoxic conditions compared to the control group, as indicated by multiple behavioral measures. Histological analysis of 2,3,5-Triphenyltetrazolium chloride (TTC) stained brain sections revealed less damage in the SCFA-fed group. We also found that Fatty Acid Binding Protein 7 (FABP7), also known as Brain Lipid Binding Protein (BLBP), a neuroprotective fatty acid binding protein, was upregulated in the brains of the SCFA-fed group. Additionally, when FABP7 was overexpressed in N2a cells, it protected the cells from injury caused by CoCl2 treatment. Overall, our data provide evidence for a neuroprotective role of P and B against hypoxic brain injury and suggest the potential of dietary supplementation with SCFAs to mitigate stroke-induced brain damage.
众所周知，肠道微生物衍生的短链脂肪酸（SCFAs）对包括认知、情绪和整体神经系统健康在内的各种大脑功能有着深远的影响。然而，它们在保护大脑免受缺氧损伤和缺血性中风方面的作用尚未得到广泛研究。在这项研究中，我们利用神经细胞系和斑马鱼模型研究了肠道中富含的两种主要 SCFAs--丙酸盐（P）和丁酸盐（B）--对缺氧再灌注损伤的影响。当神经 2a（N2a）细胞暴露于常用于模拟缺氧的化学物质 CoCl2 时，经 P 和 B 处理的细胞表现出线粒体和细胞膜活性氧（ROS）水平降低、线粒体膜电位丧失减少、caspase 激活被抑制以及细胞死亡率降低。此外，与对照组相比，喂食添加了 SCFA 的成年斑马鱼在缺氧条件下表现出更低的易感性，这体现在多种行为测量上。2,3,5-三苯基氯化四氮唑（TTC）染色脑切片的组织学分析表明，喂食 SCFA 的斑马鱼损伤较小。我们还发现，脂肪酸结合蛋白 7 (FABP7)，又称脑脂结合蛋白 (BLBP)，是一种具有神经保护作用的脂肪酸结合蛋白，在 SCFA 饲喂组的大脑中上调。此外，当 FABP7 在 N2a 细胞中过表达时，它能保护细胞免受 CoCl2 处理造成的损伤。总之，我们的数据清楚地证明了 P 和 B 对缺氧性脑损伤的神经保护作用，并表明膳食中补充 SCFAs 有可能减轻中风引起的脑损伤。
{"title":"The neuroprotective effect of short-chain fatty acids against hypoxia-reperfusion injury","authors":"Anjit K. Harijan , Retnamony Kalaiarasan , Amit Kumar Ghosh , Ruchi P. Jain , Amal Kanti Bera","doi":"10.1016/j.mcn.2024.103972","DOIUrl":"10.1016/j.mcn.2024.103972","url":null,"abstract":"<div><div>Gut microbe-derived short-chain fatty acids (SCFAs) are known to have a profound impact on various brain functions, including cognition, mood, and overall neurological health. However, their role, if any, in protecting against hypoxic injury and ischemic stroke has not been extensively studied. In this study, we investigated the effects of two major SCFAs abundant in the gut, propionate (P) and butyrate (B), on hypoxia-reperfusion injury using a neuronal cell line and a zebrafish model. Neuro 2a (N2a) cells treated with P and B exhibited reduced levels of mitochondrial and cytosolic reactive oxygen species (ROS), diminished loss of mitochondrial membrane potential, suppressed caspase activation, and lower rates of cell death when exposed to CoCl<sub>2</sub>, a chemical commonly used to simulate hypoxia. Furthermore, adult zebrafish fed SCFA-supplemented feeds showed less susceptibility to hypoxic conditions compared to the control group, as indicated by multiple behavioral measures. Histological analysis of 2,3,5-Triphenyltetrazolium chloride (TTC) stained brain sections revealed less damage in the SCFA-fed group. We also found that Fatty Acid Binding Protein 7 (FABP7), also known as Brain Lipid Binding Protein (BLBP), a neuroprotective fatty acid binding protein, was upregulated in the brains of the SCFA-fed group. Additionally, when FABP7 was overexpressed in N2a cells, it protected the cells from injury caused by CoCl<sub>2</sub> treatment. Overall, our data provide evidence for a neuroprotective role of P and B against hypoxic brain injury and suggest the potential of dietary supplementation with SCFAs to mitigate stroke-induced brain damage.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103972"},"PeriodicalIF":2.6,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.mcn.2024.103973
Xiaojin Wei , Shuxin Liu , Kai Chen , Meng Wang , Yaping Wang , Dingquan Zou , Yanying Xiao
Background
Demyelinating diseases, including multiple sclerosis (MS) and spinal cord injury (SCI), lead to significant neurological deficits primarily due to the loss of oligodendrocytes (OLs). Bone Morphogenetic Protein 7 (BMP7) is expressed abundantly in the central nervous system and previous studies showed its protective effect in reducing OL loss. In this study, we aim to explore BMP7's potential as a biomarker and therapeutic target for demyelinating diseases by investigating its expression and effects on OLs and myelin sheath integrity.
Method
We analyzed multiple Gene Expression Omnibus datasets for BMP7 expression profiles in demyelinating conditions such as MS and SCI. Experimentally, we employed a BMP7 knockdown model in rat spinal cords using adeno-associated virus8 vectors to specifically reduce BMP7 expression. Western blotting, immunofluorescence, and Nissl staining were used to assess the effect on OL and other types of cells. The structure of myelin sheath and locomotor function were evaluated using transmission electron microscopy and BBB scores, and statistical analysis included ROC curves and ANOVA to evaluate BMP7's diagnostic and therapeutic potential.
Results
BMP7 expression consistently decreased across various demyelinating models, and BMP7 knockdown led to increased OL apoptosis through the Smad1/5/9 pathway, with no apparent effect on other cell types. This reduction in OLs was associated with myelin degeneration, axonal damage, and impaired motor function.
Conclusion
The study confirms BMP7's significant involvement in the pathophysiology of demyelinating diseases and supports its potential as a therapeutic target or biomarker. Future research should focus on therapeutic strategies to enhance BMP7 function and further investigate the mechanisms by which BMP7 supports myelin integrity.
背景：脱髓鞘疾病，包括多发性硬化症（MS）和脊髓损伤（SCI），主要由于少突胶质细胞（OL）的丧失而导致严重的神经功能缺损。骨形态发生蛋白 7（BMP7）在中枢神经系统中大量表达，先前的研究表明它在减少少突胶质细胞丢失方面具有保护作用。在本研究中，我们旨在通过研究 BMP7 的表达及其对 OL 和髓鞘完整性的影响，探索其作为脱髓鞘疾病的生物标记物和治疗靶点的潜力：我们分析了多个基因表达总库数据集，以了解 BMP7 在 MS 和 SCI 等脱髓鞘疾病中的表达情况。实验中，我们使用腺相关病毒8载体在大鼠脊髓中建立了BMP7基因敲除模型，以特异性降低BMP7的表达。我们使用 Western 印迹、免疫荧光和 Nissl 染色来评估其对 OL 和其他类型细胞的影响。统计分析包括ROC曲线和方差分析，以评估BMP7的诊断和治疗潜力：结果：在各种脱髓鞘模型中，BMP7的表达量持续下降，BMP7基因敲除导致OL通过Smad1/5/9途径凋亡增加，但对其他细胞类型没有明显影响。OL的减少与髓鞘变性、轴突损伤和运动功能受损有关：该研究证实了 BMP7 在脱髓鞘疾病的病理生理学中的重要作用，并支持其作为治疗靶点或生物标志物的潜力。未来的研究应侧重于增强 BMP7 功能的治疗策略，并进一步研究 BMP7 支持髓鞘完整性的机制。
{"title":"Knockdown of BMP7 induced oligodendrocyte apoptosis, demyelination and motor function loss","authors":"Xiaojin Wei , Shuxin Liu , Kai Chen , Meng Wang , Yaping Wang , Dingquan Zou , Yanying Xiao","doi":"10.1016/j.mcn.2024.103973","DOIUrl":"10.1016/j.mcn.2024.103973","url":null,"abstract":"<div><h3>Background</h3><div>Demyelinating diseases, including multiple sclerosis (MS) and spinal cord injury (SCI), lead to significant neurological deficits primarily due to the loss of oligodendrocytes (OLs). Bone Morphogenetic Protein 7 (BMP7) is expressed abundantly in the central nervous system and previous studies showed its protective effect in reducing OL loss. In this study, we aim to explore BMP7's potential as a biomarker and therapeutic target for demyelinating diseases by investigating its expression and effects on OLs and myelin sheath integrity.</div></div><div><h3>Method</h3><div>We analyzed multiple Gene Expression Omnibus datasets for BMP7 expression profiles in demyelinating conditions such as MS and SCI. Experimentally, we employed a BMP7 knockdown model in rat spinal cords using adeno-associated virus8 vectors to specifically reduce BMP7 expression. Western blotting, immunofluorescence, and Nissl staining were used to assess the effect on OL and other types of cells. The structure of myelin sheath and locomotor function were evaluated using transmission electron microscopy and BBB scores, and statistical analysis included ROC curves and ANOVA to evaluate BMP7's diagnostic and therapeutic potential.</div></div><div><h3>Results</h3><div>BMP7 expression consistently decreased across various demyelinating models, and BMP7 knockdown led to increased OL apoptosis through the Smad1/5/9 pathway, with no apparent effect on other cell types. This reduction in OLs was associated with myelin degeneration, axonal damage, and impaired motor function.</div></div><div><h3>Conclusion</h3><div>The study confirms BMP7's significant involvement in the pathophysiology of demyelinating diseases and supports its potential as a therapeutic target or biomarker. Future research should focus on therapeutic strategies to enhance BMP7 function and further investigate the mechanisms by which BMP7 supports myelin integrity.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103973"},"PeriodicalIF":2.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1016/j.mcn.2024.103969
Ericks Sousa Soares , Letícia Yoshitome Queiroz , Ellen Gerhardt , Rui Daniel S. Prediger , Tiago Fleming Outeiro , Helena Iturvides Cimarosti
SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an in vitro model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.
{"title":"SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease","authors":"Ericks Sousa Soares , Letícia Yoshitome Queiroz , Ellen Gerhardt , Rui Daniel S. Prediger , Tiago Fleming Outeiro , Helena Iturvides Cimarosti","doi":"10.1016/j.mcn.2024.103969","DOIUrl":"10.1016/j.mcn.2024.103969","url":null,"abstract":"<div><p>SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an <em>in vitro</em> model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.</p></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"131 ","pages":"Article 103969"},"PeriodicalIF":2.6,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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