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Linking activation of synaptic NMDA receptors‐induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid‐beta peptide 将激活突触 NMDA 受体诱导的 CREB 信号与大脑皮层神经元短暂暴露于寡聚淀粉样蛋白-β肽联系起来
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1111/jnc.16222
I. Luísa Ferreira, Daniela Marinho, Valéria de Rosa, Bárbara Castanheira, Zongwei Fang, Gladys L. Caldeira, Sandra I. Mota, A. Cristina Rego
Amyloid‐beta peptide oligomers (AβO) have been considered “primum movens” for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AβO have not been clearly defined. Synaptic (Syn) N‐methyl‐d‐aspartate receptors (NMDAR) are known to activate cAMP response element‐binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+i). Thus, in this work, we analyze acute/early and long‐term AβO‐mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR‐mediated Ca2+ influx. Data also demonstrate that AβO long‐term (24 h) exposure compromises synaptic function related to Ca2+‐dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AβO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.image
淀粉样β肽寡聚体(AβO)被认为是阿尔茨海默病(AD)中最终导致选择性神经元死亡的一系列事件的 "首要动因"。然而,AβO 引发的最初事件尚未得到明确界定。已知突触(Syn)N-甲基-d-天冬氨酸受体(NMDAR)可激活cAMP反应元件结合蛋白(CREB),CREB是一种转录因子,参与细胞存活、记忆形成和突触可塑性相关基因的表达,而突触外(ESyn)NMDAR的激活则与兴奋毒性事件有关。在 AD 脑中,CREB 磷酸化/激活被证明发生了改变,同时细胞内 Ca2+ (Ca2+i) 的平衡失调。因此,在这项研究中,我们分析了急性/早期和长期 AβO 介导的 CREB 激活变化,这些变化涉及成熟大鼠皮质神经元中的 Syn 或 ESyn NMDARs。我们的研究结果表明,急性 AβO 暴露会产生磷酸化 CREB 的早期增加,反映了 CREB 的活性,这一过程是通过 Syn NMDAR 介导的 Ca2+ 流入发生的。数据还表明,长期(24 小时)暴露于 AβO 会损害与 Ca2+ 依赖性 CREB 磷酸化/激活、核 CREB 水平及相关靶基因(即 Bdnf、Gadd45γ 和 Btg2)有关的突触功能。数据表明,早期或长期暴露于 AβO 后,成熟的大脑皮层神经元会通过激活 CREB 信号通路产生双重效应,这与 Syn NMDARs 的激活有关。
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引用次数: 0
From BBB to PPP: Bioenergetic requirements and challenges for oligodendrocytes in health and disease 从 BBB 到 PPP:少突胶质细胞在健康和疾病中的生物能需求与挑战
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1111/jnc.16219
Milton Guilherme Forestieri Fernandes, Florian Pernin, Jack P. Antel, Timothy E. Kennedy
Mature myelinating oligodendrocytes, the cells that produce the myelin sheath that insulates axons in the central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy to execute action potentials, while the energy needs of oligodendrocytes are directed toward building the lipid‐rich components of myelin and supporting neuronal metabolism by transferring glycolytic products to axons as additional fuel. The utilization of energy metabolites in the brain parenchyma is tightly regulated to meet the needs of different cell types. Disruption of the supply of metabolites can lead to stress and oligodendrocyte injury, contributing to various neurological disorders, including some demyelinating diseases. Understanding the physiological properties, structures, and mechanisms involved in oligodendrocyte energy metabolism, as well as the relationship between oligodendrocytes and neighboring cells, is crucial to investigate the underlying pathophysiology caused by metabolic impairment in these disorders. In this review, we describe the particular physiological properties of oligodendrocyte energy metabolism and the response of oligodendrocytes to metabolic stress. We delineate the relationship between oligodendrocytes and other cells in the context of the neurovascular unit, and the regulation of metabolite supply according to energetic needs. We focus on the specific bioenergetic requirements of oligodendrocytes and address the disruption of metabolic energy in demyelinating diseases. We encourage further studies to increase understanding of the significance of metabolic stress on oligodendrocyte injury, to support the development of novel therapeutic approaches for the treatment of demyelinating diseases.image
成熟的髓鞘化少突胶质细胞是产生髓鞘的细胞,髓鞘在中枢神经系统中对轴突起绝缘作用,与神经元相比,少突胶质细胞对能量和新陈代谢的需求各不相同。神经元需要大量能量来执行动作电位,而少突胶质细胞的能量需求则用于构建髓鞘中富含脂质的成分,并通过将糖酵解产物转移到轴突作为额外燃料来支持神经元的新陈代谢。脑实质中能量代谢产物的利用受到严格调控,以满足不同类型细胞的需要。代谢产物供应的中断会导致压力和少突胶质细胞损伤,从而引发各种神经系统疾病,包括一些脱髓鞘疾病。了解少突胶质细胞能量代谢所涉及的生理特性、结构和机制,以及少突胶质细胞与邻近细胞之间的关系,对于研究这些疾病中代谢障碍所导致的潜在病理生理学至关重要。在这篇综述中,我们描述了少突胶质细胞能量代谢的特殊生理特性以及少突胶质细胞对代谢压力的反应。我们描述了少突胶质细胞与神经血管单元中其他细胞之间的关系,以及根据能量需求对代谢物供应的调节。我们重点研究了少突胶质细胞对生物能的特殊需求,并探讨了脱髓鞘疾病对代谢能的破坏。我们鼓励开展进一步研究,以加深了解代谢压力对少突胶质细胞损伤的重要意义,从而为开发治疗脱髓鞘疾病的新型疗法提供支持。
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引用次数: 0
Increased forebrain EAAT3 expression confers resilience to chronic stress. 增加前脑EAAT3的表达可增强对慢性压力的适应能力
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-08 DOI: 10.1111/jnc.16216
Nicolás M Ardiles, Vissente Tapia-Cuevas, Sebastián F Estay, Alejandro Alcaino, Victoria B Velásquez, Ramón Sotomayor-Zárate, Andrés E Chávez, Pablo R Moya

Depression is a disabling and highly prevalent psychiatric illness. Multiple studies have linked glutamatergic dysfunction with the pathophysiology of depression, but the exact alterations in the glutamatergic system that contribute to depressive-like behaviors are not fully understood. Recent evidence suggests that a decreased level in neuronal glutamate transporter (EAAT3), known to control glutamate levels and limit the activation of glutamate receptors at synaptic sites, may contribute to the manifestation of a depressive phenotype. Here, we tested the possibility that increased EAAT3 expression at excitatory synapses could reduce the susceptibility of mice to develop depressive-like behaviors when challenged to a 5-week unpredictable chronic mild stress (UCMS) protocol. Mice overexpressing EAAT3 in the forebrain (EAAT3glo/CMKII) and control littermates (EAAT3glo) were assessed for depressive-like behaviors and long-term memory performance after being subjected to UCMS conditions. We found that, after UCMS, EAAT3glo/CMKII mice did not exhibit depressive-like behaviors or memory alterations observed in control mice. Moreover, we found that EAAT3glo/CMKII mice did not show alterations in phasic dopamine release in the nucleus accumbens neither in long-term synaptic plasticity in the CA1 region of the hippocampus after UCMS, as observed in control littermates. Altogether these results suggest that forebrain EAAT3 overexpression may be related to a resilient phenotype, both at behavioral and functional level, to the deleterious effect of chronic stress, highlighting the importance of neuronal EAAT3 in the pathophysiology of depressive-like behaviors.

抑郁症是一种致残性、高发病率的精神疾病。多项研究表明,谷氨酸能功能障碍与抑郁症的病理生理学有关,但导致抑郁样行为的谷氨酸能系统的确切改变尚不完全清楚。最近的证据表明,神经元谷氨酸转运体(EAAT3)水平的降低可能会导致抑郁表型的表现,已知EAAT3能控制谷氨酸水平并限制突触部位谷氨酸受体的激活。在这里,我们测试了在兴奋性突触处增加 EAAT3 表达是否能降低小鼠在接受为期 5 周的不可预测慢性温和应激(UCMS)方案挑战时产生抑郁样行为的易感性。我们对前脑过表达 EAAT3 的小鼠(EAAT3glo/CMKII)和对照组小鼠(EAAT3glo)进行了抑郁样行为和长期记忆表现的评估。我们发现,在 UCMS 之后,EAAT3glo/CMKII 小鼠没有表现出对照组小鼠所观察到的抑郁样行为或记忆改变。此外,我们还发现,EAAT3glo/CMKII 小鼠在 UCMS 后并没有表现出与对照组同窝小鼠一样的凹凸核多巴胺阶段性释放的改变,也没有表现出海马 CA1 区长期突触可塑性的改变。总之,这些结果表明,前脑 EAAT3 的过度表达可能与一种在行为和功能水平上对慢性应激的有害影响具有恢复力的表型有关,突出了神经元 EAAT3 在抑郁样行为的病理生理学中的重要性。
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引用次数: 0
Visualization of myelin-forming oligodendrocytes in the adult mouse brain. 成年小鼠大脑中髓鞘形成少突胶质细胞的可视化。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1111/jnc.16218
Kiichi Yokoyama, Yuichi Hiraoka, Yoshifumi Abe, Kenji F Tanaka

Oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs) is considered to result in two populations: premyelinating and myelinating OLs. Recent single-cell RNA sequence data subdivided these populations into newly formed (NFOLs), myelin-forming (MFOLs), and mature (MOLs) oligodendrocytes. However, which newly proposed population corresponds to premyelinating or myelinating OLs is unknown. We focused on the NFOL-specific long non-coding oligodendrocyte 1 gene (LncOL1) and sought to label NFOLs under the control of the LncOL1 promoter using a tetracycline-controllable gene induction system. We demonstrated that LncOL1 was expressed by premyelinating OLs and that the MFOL-specific gene, Ctps, was not, indicating that NFOLs correspond to premyelinating OLs and that MFOLs and MOLs correspond to myelinating OLs. We then generated a LncOL1-tTA mouse in which a tetracycline transactivator (tTA) cassette was inserted downstream from the LncOL1 transcription initiation site. By crossing the LncOL1-tTA mice with tetO reporter mice, we generated LncOL1-tTA::tetO-yellow fluorescent protein (YFP) double-transgenic (LncOL1-YFP) mice. Although LncOL1 is non-coding, YFP was detected in LncOL1-YFP mice, indicating successful tTA translation. Unexpectedly, we found that the morphology of LncOL1-tTA-driven YFP+ cells was distinct from that of LncOL1+ premyelinating OLs and that the labeled cells instead appeared as myelinating OLs. We demonstrated from their RNA expression that YFP-labeled OLs were MFOLs, but not MOLs. Using the unique property of delayed YFP induction, we sought to determine whether MFOLs are constantly supplied from OPCs and differentiate into MOLs, or whether MFOLs pause their differentiation and sustain this stage in the adult brain. To achieve this objective, we irradiated adult LncOL1-YFP brains with X-rays to deplete dividing OPCs and their progeny. The irradiation extinguished YFP-labeled OLs, indicating that adult OPCs differentiated into MOLs during a single period. We established a new transgenic mouse line that genetically labels MFOLs, providing a reliable tool for investigating the dynamics of adult oligodendrogenesis.

少突胶质细胞(OL)从少突胶质细胞前体细胞(OPCs)分化而来,被认为会产生两个群体:前髓鞘化少突胶质细胞和髓鞘化少突胶质细胞。最近的单细胞 RNA 序列数据将这些群体细分为新形成(NFOLs)、髓鞘形成(MFOLs)和成熟(MOLs)少突胶质细胞。然而,哪个新提出的群体对应于髓鞘化前或髓鞘化的少突胶质细胞尚不清楚。我们重点研究了NFOL特异性长非编码少突胶质细胞1基因(LncOL1),并试图利用四环素可控基因诱导系统对LncOL1启动子控制下的NFOL进行标记。我们证明髓鞘前OLs表达LncOL1,而MFOL特异性基因Ctps不表达,这表明NFOLs对应于髓鞘前OLs,而MFOLs和MOLs对应于髓鞘OLs。随后,我们生成了一种LncOL1-tTA小鼠,其中在LncOL1转录起始位点下游插入了一个四环素转录激活剂(tTA)盒。通过将 LncOL1-tTA 小鼠与 tetO 报告小鼠杂交,我们产生了 LncOL1-tTA::tetO-黄色荧光蛋白(YFP)双转基因(LncOL1-YFP)小鼠。虽然 LncOL1 是非编码,但在 LncOL1-YFP 小鼠中检测到了 YFP,这表明 tTA 翻译成功。意想不到的是,我们发现 LncOL1-tTA 驱动的 YFP+ 细胞的形态与 LncOL1+ 髓鞘化前 OL 的形态不同,标记的细胞显示为髓鞘化 OL。我们通过其 RNA 表达证明,YFP 标记的 OL 是 MFOL,而不是 MOL。利用延迟诱导 YFP 的独特特性,我们试图确定 MFOLs 是否不断从 OPCs 中获得供应并分化为 MOLs,或者 MFOLs 是否暂停分化并在成人大脑中维持这一阶段。为了实现这一目标,我们用 X 射线照射 LncOL1-YFP 成年人大脑,以消耗正在分裂的 OPCs 及其后代。照射后,YFP标记的OL熄灭,表明成年OPC在一个时期内分化为MOL。我们建立了一个新的转基因小鼠品系,该品系可对MFOLs进行基因标记,为研究成体少突发生的动态提供了可靠的工具。
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引用次数: 0
Relaxin family peptide receptor 3 (RXFP3) expressing cells in the zona incerta/lateral hypothalamus augment behavioural arousal. 下丘脑内侧带/外侧的松弛素家族肽受体3(RXFP3)表达细胞可增强行为唤醒。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1111/jnc.16217
Brandon K Richards, Sarah S Ch'ng, Ariel B Simon, Terence Y Pang, Jee Hyun Kim, Andrew J Lawrence, Christina J Perry

Fear-related psychopathologies, such as post-traumatic stress disorder, are linked to dysfunction in neural circuits that govern fear memory and arousal. The lateral hypothalamus (LH) and zona incerta (ZI) regulate fear, but our understanding of the precise neural circuits and cell types involved remains limited. Here, we examined the role of relaxin family peptide receptor 3 (RXFP3) expressing cells in the LH/ZI in conditioned fear expression and general arousal in male RXFP3-Cre mice. We found that LH/ZI RXFP3+ (LH/ZIRXFP3) cells projected strongly to fear learning, stress, and arousal centres, notably, the periaqueductal grey, lateral habenula, and nucleus reuniens. These cells do not express hypocretin/orexin or melanin-concentrating hormone but display putative efferent connectivity with LH hypocretin/orexin+ neurons and dopaminergic A13 cells. Following Pavlovian fear conditioning, chemogenetically activating LH/ZIRXFP3 cells reduced fear expression (freezing) overall but also induced jumping behaviour and increased locomotor activity. Therefore, the decreased freezing was more likely to reflect enhanced arousal rather than reduced fear. Indeed, stimulating these cells produced distinct patterns of coactivation between several motor, stress, and arousal regions, as measured by Fos expression. These results suggest that activating LH/ZIRXFP3 cells generates brain-wide activation patterns that augment behavioural arousal.

与恐惧有关的精神病理学,如创伤后应激障碍,与支配恐惧记忆和唤醒的神经回路功能障碍有关。外侧下丘脑(LH)和内侧下丘脑(ZI)调节恐惧,但我们对其中涉及的精确神经回路和细胞类型的了解仍然有限。在这里,我们研究了雄性 RXFP3-Cre 小鼠 LH/ZI 中表达弛缓素家族肽受体 3(RXFP3)的细胞在条件性恐惧表达和一般唤醒中的作用。我们发现,LH/ZI RXFP3+(LH/ZIRXFP3)细胞强烈投射到恐惧学习、应激和唤醒中枢,尤其是咽周灰质、外侧哈文脑和团圆核。这些细胞不表达视网膜下素/视网膜素或黑色素浓缩激素,但显示出与LH视网膜下素/视网膜素+神经元和多巴胺能A13细胞的传出连接。在巴甫洛夫恐惧条件反射后,化学激活 LH/ZIRXFP3 细胞可减少恐惧表达(冻结),但也可诱导跳跃行为和增加运动活动。因此,冻结的减少更有可能反映了唤醒的增强,而不是恐惧的减少。事实上,刺激这些细胞会在多个运动、应激和唤醒区域之间产生不同的共激活模式,这是由 Fos 表达所衡量的。这些结果表明,激活LH/ZIRXFP3细胞可产生全脑激活模式,从而增强行为唤醒。
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引用次数: 0
Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins. 淀粉样肽和其他生物毒素对线粒体膜的分隔作用。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1111/jnc.16213
Neville Vassallo

Mitochondria are essential organelles known to serve broad functions, including in cellular metabolism, calcium buffering, signaling pathways and the regulation of apoptotic cell death. Maintaining the integrity of the outer (OMM) and inner mitochondrial membranes (IMM) is vital for mitochondrial health. Cardiolipin (CL), a unique dimeric glycerophospholipid, is the signature lipid of energy-converting membranes. It plays a significant role in maintaining mitochondrial architecture and function, stabilizing protein complexes and facilitating efficient oxidative phosphorylation (OXPHOS) whilst regulating cytochrome c release from mitochondria. CL is especially enriched in the IMM and at sites of contact between the OMM and IMM. Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid-β, tau and α-synuclein, which form metastable toxic oligomeric species that interact with biological membranes. Electrophysiological studies have shown that these oligomers form ion-conducting nanopores in membranes mimicking the IMM's phospholipid composition. Poration of mitochondrial membranes disrupts the ionic balance, causing osmotic swelling, loss of the voltage potential across the IMM, release of pro-apoptogenic factors, and leads to cell death. The interaction between CL and amyloid oligomers appears to favour their membrane insertion and pore formation, directly implicating CL in amyloid toxicity. Additionally, pore formation in mitochondrial membranes is not limited to amyloid proteins and peptides; other biological peptides, as diverse as the pro-apoptotic Bcl-2 family members, gasdermin proteins, cobra venom cardiotoxins and bacterial pathogenic toxins, have all been described to punch holes in mitochondria, contributing to cell death processes. Collectively, these findings underscore the vulnerability of mitochondria and the involvement of CL in various pathogenic mechanisms, emphasizing the need for further research on targeting CL-amyloid interactions to mitigate mitochondrial dysfunction.

线粒体是重要的细胞器,具有广泛的功能,包括细胞代谢、钙缓冲、信号通路和细胞凋亡调控。保持线粒体外膜(OMM)和内膜(IMM)的完整性对线粒体的健康至关重要。心磷脂(CL)是一种独特的二聚甘油磷脂,是能量转换膜的标志性脂质。它在维持线粒体结构和功能、稳定蛋白质复合物、促进高效氧化磷酸化(OXPHOS)以及调节线粒体释放细胞色素 c 方面发挥着重要作用。CL尤其富集在线粒体内膜和线粒体外膜与线粒体内膜的接触部位。阿尔茨海默氏症和帕金森氏症等蛋白质错误折叠疾病涉及淀粉样蛋白-β、tau 和 α-突触核蛋白等淀粉样蛋白肽,这些肽会形成可转移的有毒低聚物,与生物膜相互作用。电生理学研究表明,这些低聚物会在模仿 IMM 磷脂成分的膜上形成离子传导纳米孔。线粒体膜上的孔破坏了离子平衡,导致渗透膨胀、跨线粒体膜的电压电位下降、促凋亡因子释放并导致细胞死亡。CL 与淀粉样蛋白寡聚体之间的相互作用似乎有利于它们的膜插入和孔隙形成,这直接表明 CL 与淀粉样蛋白的毒性有关。此外,线粒体膜孔隙的形成并不局限于淀粉样蛋白和肽,其他生物肽,如促凋亡的 Bcl-2 家族成员、gasdermin 蛋白、眼镜蛇毒心脏毒素和细菌致病毒素,都被描述为在线粒体上打孔,导致细胞死亡的过程。总之,这些发现强调了线粒体的脆弱性以及CL在各种致病机制中的参与,强调了进一步研究针对CL-淀粉样蛋白相互作用以缓解线粒体功能障碍的必要性。
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引用次数: 0
Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice. 曲利卢唑可挽救 3xTg-AD 小鼠的谷氨酸能缺陷、淀粉样蛋白和 tau 病理学以及突触和记忆损伤。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1111/jnc.16215
Jeremiah Pfitzer, Priyanka D Pinky, Savannah Perman, Emma Redmon, Luca Cmelak, Vishnu Suppiramaniam, Vladimir Coric, Irfan A Qureshi, Michael W Gramlich, Miranda N Reed

Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aβ) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aβ models, suggesting the changes in pool size may be due to Aβ and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer's disease.

阿尔茨海默病(AD)是一种神经退行性疾病,其临床症状与谷氨酸能突触的丧失密切相关。阿尔茨海默病晚期由于神经元缺失,谷氨酸水平明显下降,而在早期,谷氨酸的病理性积累和亢进会导致阿尔茨海默病的病理变化和认知功能障碍。越来越多的人认识到,突触前功能障碍,尤其是突触小泡(SV)的改变,在介导这种早期亢进中起着关键作用。在本研究中,我们试图确定同时表现出β-淀粉样蛋白(Aβ)和tau相关病理变化的3xTg小鼠AD模型是否会表现出与之前在淀粉样蛋白或tau模型中分别观察到的类似突触前变化。我们使用 3xTg 小鼠的海马培养物来确定突触前囊泡谷氨酸转运体(VGlut)和谷氨酸是否在突触水平增加,同时控制突触后活动。我们观察到,3xTg 海马培养物表现出与谷氨酸释放增加相关的 VGlut1 增加,这与之前在 tau 小鼠模型培养物中观察到的结果类似。然而,3xTg 培养物中 SV 池的大小也增加了,这是之前在 tau 小鼠模型中没有观察到的,但在 Aβ 模型中观察到了,这表明池大小的变化可能是由于 Aβ 而不是 tau 引起的。其次,我们试图确定使用谷氨酸调节剂利鲁唑的新型第三代三肽原药曲利鲁唑治疗是否能减少 VGlut1 和谷氨酸的释放,从而恢复 8 个月大的 3xTg 小鼠的认知障碍。使用曲利卢唑治疗可减少 VGlut1 的表达,降低谷氨酸的基础释放和诱发释放,并恢复 3xTg 小鼠的认知障碍。这些发现共同表明突触前改变是阿兹海默病的早期事件,是治疗干预的潜在靶点,这些结果支持了谷氨酸调节药物(如曲利卢唑)治疗阿兹海默病的前景。
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引用次数: 0
Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review. CHRNA4 和 CHRNB2 缺乏症患者的临床、分子、生理和治疗特征:系统综述。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1111/jnc.16200
Abbas Jalaiei, Mohammad Reza Asadi, Yousef Daneshmandpour, Maryam Rezazadeh, Soudeh Ghafouri-Fard

The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.

α4β2 nAChRs 是控制神经递质释放的重要离子通道,在各种生理和病理过程中发挥作用。CHRNA4 编码α4-nAChRs,而 CHRNB2 编码β2-nAChRs。最近的研究发现,在患有注意力缺失症(AD)、多动症(ADHD)、肌萎缩性脊髓侧索硬化症(ALS)、帕金森病(PD)和大脑异常等疾病的患者中,α4β2-nAChRs 存在不同的变体。我们按照六阶段方法结构并遵循 PRISMA 指南进行了范围界定综述。我们使用相关关键词对截至 2023 年 10 月 2 日的文章进行了系统综述。在本摘要中,我们介绍了所报道的临床症状、CHRNA4 和 CHRNB2 的基因和蛋白结构、这些基因的突变、遗传模式、CHRNA4 和 CHRNB2 的突变和多态性对功能的影响以及这些疾病的流行病学。最新研究表明,nAChRs 可能在神经退行性疾病中扮演重要角色,可能通过尚未发现的调节途径影响神经元功能。研究神经退行性疾病中的 nAChRs 如何与疾病相关的聚集体相互作用,可能会为这些疾病带来新的治疗方案。
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引用次数: 0
Misprogramming of glucose metabolism impairs recovery of hippocampal slices from neuronal GLT-1 knockout mice and contributes to excitotoxic injury through mitochondrial superoxide production. 葡萄糖代谢的错误编程会损害神经元GLT-1基因敲除小鼠海马切片的恢复,并通过线粒体超氧化物的产生导致兴奋性毒性损伤。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1111/jnc.16205
S Li, J Wang, J V Andersen, B I Aldana, B Zhang, E V Prochownik, P A Rosenberg

We have previously reported a failure of recovery of synaptic function in the CA1 region of acute hippocampal slices from mice with a conditional neuronal knockout (KO) of GLT-1 (EAAT2, Slc1A2) driven by synapsin-Cre (synGLT-1 KO). The failure of recovery of synaptic function is due to excitotoxic injury. We hypothesized that changes in mitochondrial metabolism contribute to the heightened vulnerability to excitotoxicity in the synGLT-1 KO mice. We found impaired flux of carbon from 13C-glucose into the tricarboxylic acid cycle in synGLT-1 KO cortical and hippocampal slices compared with wild-type (WT) slices. In addition, we found downregulation of the neuronal glucose transporter GLUT3 in both genotypes. Flux of carbon from [1,2-13C]acetate, thought to be astrocyte-specific, was increased in the synGLT-KO hippocampal slices but not cortical slices. Glycogen stores, predominantly localized to astrocytes, are rapidly depleted in slices after cutting, and are replenished during ex vivo incubation. In the synGLT-1 KO, replenishment of glycogen stores during ex vivo incubation was compromised. These results suggest both neuronal and astrocytic metabolic perturbations in the synGLT-1 KO slices. Supplementing incubation medium during recovery with 20 mM D-glucose normalized glycogen replenishment but had no effect on recovery of synaptic function. In contrast, 20 mM non-metabolizable L-glucose substantially improved recovery of synaptic function, suggesting that D-glucose metabolism contributes to the excitotoxic injury in the synGLT-1 KO slices. L-lactate substitution for D-glucose did not promote recovery of synaptic function, implicating mitochondrial metabolism. Consistent with this hypothesis, phosphorylation of pyruvate dehydrogenase, which decreases enzyme activity, was increased in WT slices during the recovery period, but not in synGLT-1 KO slices. Since metabolism of glucose by the mitochondrial electron transport chain is associated with superoxide production, we tested the effect of drugs that scavenge and prevent superoxide production. The superoxide dismutase/catalase mimic EUK-134 conferred complete protection and full recovery of synaptic function. A site-specific inhibitor of complex III superoxide production, S3QEL-2, was also protective, but inhibitors of NADPH oxidase were not. In summary, we find that the failure of recovery of synaptic function in hippocampal slices from the synGLT-1 KO mouse, previously shown to be due to excitotoxic injury, is caused by production of superoxide by mitochondrial metabolism.

我们以前曾报道过,在突触素-Cre(synapsin-Cre,synGLT-1 KO)驱动的条件性神经元敲除(KO)GLT-1(EAAT2,Slc1A2)的小鼠急性海马切片的CA1区,突触功能未能恢复。突触功能无法恢复的原因是兴奋毒性损伤。我们推测,线粒体代谢的变化是导致 synGLT-1 KO 小鼠更易受兴奋毒性伤害的原因。与野生型(WT)切片相比,我们发现在 synGLT-1 KO 小鼠的皮质和海马切片中,13C-葡萄糖进入三羧酸循环的碳通量受损。此外,我们还发现两种基因型的神经元葡萄糖转运体 GLUT3 均出现下调。在 synGLT-KO 海马切片中,被认为是星形胶质细胞特异性的 [1,2-13C] 乙酸的碳通量增加了,但在大脑皮层切片中却没有增加。糖原储存主要定位于星形胶质细胞,切片后会迅速耗尽,并在体外培养过程中得到补充。在 synGLT-1 KO 中,体内外培养期间糖原储存的补充受到影响。这些结果表明,在 synGLT-1 KO 切片中,神经元和星形胶质细胞的代谢都受到了干扰。在恢复期间用 20 mM D-葡萄糖补充培养基可使糖原补充正常化,但对突触功能的恢复没有影响。与此相反,20 mM 不可代谢的 L-葡萄糖大大改善了突触功能的恢复,这表明 D-葡萄糖代谢是 synGLT-1 KO 切片兴奋毒性损伤的原因之一。用 L-乳酸替代 D-葡萄糖并不能促进突触功能的恢复,这与线粒体代谢有关。与这一假设相一致的是,丙酮酸脱氢酶的磷酸化会降低酶的活性,而在恢复期间,WT 切片的丙酮酸脱氢酶的磷酸化会增加,但在 synGLT-1 KO 切片中则不会。由于线粒体电子传递链的葡萄糖代谢与超氧化物的产生有关,我们测试了清除和防止超氧化物产生的药物的效果。超氧化物歧化酶/催化酶模拟物 EUK-134 能提供完全保护并完全恢复突触功能。复合体 III 超氧化物产生的位点特异性抑制剂 S3QEL-2 也具有保护作用,但 NADPH 氧化酶抑制剂则没有保护作用。总之,我们发现,之前被证明是兴奋毒性损伤导致的 synGLT-1 KO 小鼠海马切片突触功能恢复失败,是由线粒体代谢产生的超氧化物引起的。
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引用次数: 0
A tribute to Arne Schousboe's contributions to neurochemistry and his innovative and enduring research in GABA, glutamate, and brain energy metabolism. 向 Arne Schousboe 对神经化学的贡献以及他在 GABA、谷氨酸和脑能量代谢方面的创新和持久研究致敬。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-26 DOI: 10.1111/jnc.16207
Mary C McKenna, Ursula Sonnewald, Helle S Waageptersen, H Steve White

This is a tribute to Arne Schousboe, Professor Emeritus at the University of Copenhagen, an eminent neurochemist and neuroscientist who was a leader in the fields of GABA, glutamate, and brain energy metabolism. Arne was known for his keen intellect, his wide-ranging expertise in neurochemistry and neuropharmacology of GABA and glutamate and brain energy metabolism. Arne was also known for his strong leadership, his warm and engaging personality and his enjoyment of fine wine and great food shared with friends, family, and colleagues. Sadly, Arne passed away on February 27, 2024, after a short illness. He is survived by his wife Inger Schousboe, his two children, and three wonderful grandchildren. His death is a tremendous loss to the neuroscience community. He will be greatly missed by his friends, family, and colleagues. Some of the highlights of Arne's career are described in this tribute.

这是对哥本哈根大学名誉教授、著名神经化学家和神经科学家阿尔纳-舒斯博(Arne Schousboe)的悼念,他是 GABA、谷氨酸和脑能量代谢领域的领军人物。阿恩以其敏锐的智慧、在 GABA 和谷氨酸的神经化学和神经药理学以及脑能量代谢方面的广泛专业知识而闻名。阿恩还以其强大的领导力、热情和富有感染力的个性以及喜欢与朋友、家人和同事分享美酒佳肴而闻名。不幸的是,阿恩于 2024 年 2 月 27 日因病去世。他的妻子英格-舒斯博(Inger Schousboe)、两个孩子和三个可爱的孙子孙女都健在。他的去世是神经科学界的巨大损失。他的朋友、家人和同事都会深深地怀念他。本悼文介绍了阿恩职业生涯中的一些亮点。
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引用次数: 0
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Journal of Neurochemistry
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