Liquid-liquid phase separation of protein tau: An emerging process in Alzheimer's disease pathogenesis

蛋白质tau的液-液相分离：阿尔茨海默病发病机制中的一个新过程

Tau droplet has been shown to mature into insoluble aggregates suggesting that this process may precede and induce neurodegeneration in AD. Here we review major factors involved in liquid droplet formation within a cell. Additionally, we highlight recent findings concerning tau aggregation following phase separation in AD, along with the potential therapeutic strategies that could be explored in this process against the progression of this pathology.

研究表明，tau液滴可以成熟为不可溶的聚集体，这表明这一过程可能先于并诱导AD的神经变性。在这里，我们回顾了细胞内液滴形成的主要因素。此外，我们重点介绍了最近关于阿尔茨海默病时相分离后tau聚集的发现，以及在这一过程中可以探索的潜在治疗策略，以对抗这种病理的进展。

REF: Ainani H, Bouchmaa N, Ben Mrid R, El Fatimy R. Liquid-liquid phase separation of protein tau: An emerging process in Alzheimer's disease pathogenesis. Neurobiol Dis. 2023;178:106011. doi:10.1016/j.nbd.2023.106011 PMID: 36702317

How does neurovascular unit dysfunction contribute to multiple sclerosis?

神经血管单位功能障碍如何导致多发性硬化症？

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system (CNS) and the most common non-traumatic cause of neurological disability in young adults. We revisit multiple sclerosis risk factors and multiple sclerosis pathophysiology and highlight the known and potential roles of neurovascular unit dysfunction in multiple sclerosis development and disease progression. We also evaluate the suitability of the neurovascular unit as a potential target for future disease modifying therapies for multiple sclerosis.

多发性硬化症是一种中枢神经系统(CNS)炎症性脱髓鞘疾病，是导致年轻人神经功能障碍的最常见的非创伤性原因。我们回顾了多发性硬化症的危险因素和多发性硬化症的病理生理学，并强调了神经血管单位功能障碍在多发性硬化症的发展和疾病进展中的已知和潜在的作用。我们还评估了神经血管单位作为未来多发性硬化症疾病修饰治疗的潜在靶点的适宜性。

REF: Cashion JM, Young KM, Sutherland BA. How does neurovascular unit dysfunction contribute to multiple sclerosis?. Neurobiol Dis. 2023;178:106028. doi:10.1016/j.nbd.2023.106028 PMID: 36736923

The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression

携带PSEN1基因突变的神经元的转录图谱揭示了细胞外基质成分和非编码基因表达的变化

Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene.

阿尔茨海默病(AD)是一种进行性和不可逆转的大脑疾病，可因环境、遗传和表观遗传因素的复杂组合而零星发生，也可因特定基因的罕见遗传变异(家族性AD或FAD)而发生。AD的一个关键特征是淀粉样β蛋白(Aβ)和Tau过度磷酸化的缠结在大脑中积累，但其潜在的发病机制和相互依赖仍然知之甚少。在这里，我们识别和表征了与早老素-1(PSEN1)基因的两个FAD突变(A79V和L150P)相关的基因表达变化。

REF: Corsi GI, Gadekar VP, Haukedal H, et al. The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression. Neurobiol Dis. 2023;178:105980. doi:10.1016/j.nbd.2022.105980 PMID: 36572121

Global brain c-Fos profiling reveals major functional brain networks rearrangements after alcohol reexposure

全球脑c-Fos图谱显示酒精重新暴露后的主要脑功能网络重排

Many fundamental questions on alcohol use disorder (AUD) are frequently difficult to address by examining a single brain structure, but should be viewed from the whole brain perspective. c-Fos is a marker of neuronal activation. Global brain c-Fos profiling in rodents represents a promising platform to study brain functional networks rearrangements in AUD. We used a mouse model of alcohol drinking in IntelliCage. Alcohol reexposure leads to a massive change of brain modularity including a formation of numerous smaller functional modules grouping structures involved in addiction development. Binge drinking can lead to substantial functional remodeling in the brain. We provide a list of structures that can be used as a target in pharmacotherapy but also point to the networks and modules that can hold therapeutic potential demonstrated by a clinical trial in patients.

酒精使用障碍(AUD)的许多基本问题往往很难通过检查单一的大脑结构来解决，但应该从整个大脑的角度来看待。C-Fos是神经元激活的标志。啮齿类动物的全球脑c-Fos图谱是研究AUD脑功能网络重排的一个很有前途的平台。我们在IntelliCage中使用了一个饮酒的小鼠模型。再次接触酒精会导致大脑模块化的巨大变化，包括形成许多较小的功能模块，将参与成瘾发展的结构分组。酗酒会导致大脑的实质性功能重塑。我们提供了一个可用作药物治疗靶点的结构列表，但也指出了可以保持治疗潜力的网络和模块，这些网络和模块已被患者的临床试验证明。

REF: Stefaniuk M, Pawłowska M, Barański M, et al. Global brain c-Fos profiling reveals major functional brain networks rearrangements after alcohol reexposure. Neurobiol Dis. 2023;178:106006. doi:10.1016/j.nbd.2023.106006 PMID: 36682503

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

RTg4510自闭症小鼠模型中视觉驱动的神经元整体动力学的早期损害

In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Dysfunction of cortical pyramidal function was also reflected in a reduction of basal theta oscillations and enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol in rTg4510 mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as biomarker candidates in early stages of neurodegenerative tauopathies.

在本研究中，我们研究了rTg4510神经变性模型小鼠初级视皮层锥体神经元群在基础状态和光诱发状态下的振荡节律和单细胞钙活动。我们发现它们的响应性和整体活性降低，这对GABA能调节不敏感。尽管皮质锥体神经元的基础状态共激活增强，但观察到输入-输出同步性的丧失。皮质锥体功能障碍也反映在rTg4510小鼠的基础theta振荡减少和对亚惊厥剂量戊四氮的敏感性增加上。我们的结果揭示了视觉皮质锥体神经元处理的损害，并将异常振荡定义为神经退行性疾病早期阶段的生物标记物候选。

REF: Parka A, Degel C, Dreyer J, et al. Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model. Neurobiol Dis. 2023;178:106012. doi:10.1016/j.nbd.2023.106012 PMID: 36696792

Early derangement of axonal mitochondria occurs in a mouse model of progressive but not relapsing-remitting multiple sclerosis

进展性但不复发-缓解型多发性硬化症小鼠模型中轴突线粒体早期排列紊乱

Derangement of axonal mitochondrial bioenergetics occurs during progressive multiple sclerosis (PMS). However, whether this is a delayed epiphenomenon or an early causative event of disease progression waits to be understood. Answering this question might further our knowledge of mechanisms underlying neurobiology of PMS and related therapy. We provide here the first evidence that axonal-restricted derangement of mitochondrial homeostasis already occurs during the asymptomatic state exclusively in a mouse model of PMS. Data further our understanding of mechanisms related to EAE progression, and point to very early axonal mitochondrial dysfunction as central to the neuropathogenesis of MS evolution.

进行性多发性硬化症(PMS)发生轴突线粒体生物能量学紊乱。然而，这是一种延迟的副现象，还是疾病进展的早期致因事件，还有待于了解。回答这个问题可能会加深我们对经前综合征神经生物学机制和相关治疗的了解。在这里，我们提供了第一个证据，表明在无症状状态下，线粒体动态平衡的轴突限制性紊乱已经专门发生在经前综合征的小鼠模型中。数据进一步加深了我们对EAE进展相关机制的理解，并指出非常早期的轴突线粒体功能障碍是MS进化的神经发病机制的核心。

REF: Buonvicino D, Ranieri G, Guasti D, et al. Early derangement of axonal mitochondria occurs in a mouse model of progressive but not relapsing-remitting multiple sclerosis. Neurobiol Dis. 2023;178:106015. doi:10.1016/j.nbd.2023.106015 PMID: 36702320

Hippocampal glucocorticoid receptors modulate status epilepticus severity

海马糖皮质激素受体对癫痫持续状态的调节作用

The study is to assess whether loss of GR affected susceptibility to SE-induced cell death, within-animal analyses were conducted comparing local GR knockdown rates to local cell loss. GR knockdown did not affect the degree of localized neuronal loss, suggesting cell-intrinsic GR signaling neither protects nor sensitizes neurons to acute SE-induced death. Overall, the findings reveal that hippocampal GRs exert an anti-convulsant role in both males and females in the early stages of SE, followed by a switch to a pro-convulsive role for males only. Findings reveal an unexpected complexity in the interaction between hippocampal GR activation and the progression of SE.

为了评估GR缺失是否影响SE诱导的细胞死亡的易感性，进行了动物内分析，比较了局部GR敲除率和局部细胞损失。GR基因敲除不影响局部神经元丢失的程度，提示细胞内源性GR信号既不能保护神经元，也不能使神经元对SE诱导的急性死亡敏感。总体而言，研究结果显示，在SE的早期阶段，海马区GRs对男性和女性都起到了抗惊厥的作用，随后转变为只对男性起到促惊厥的作用。研究结果揭示了海马区GR激活和SE进展之间相互作用的意想不到的复杂性。

REF: Kraus KL, Nawreen N, Godale CM, et al. Hippocampal glucocorticoid receptors modulate status epilepticus severity. Neurobiol Dis. 2023;178:106014. doi:10.1016/j.nbd.2023.106014 PMID: 36702319

Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy

α-突触核蛋白的过表达干扰突触核病小鼠模型的APP和内体轴突运输

Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN-/-) mouse model. Our results demonstrate that expression of GFP-hASYN in primary neurons derived from a transgenic mouse impaired axonal trafficking and processing of APP. In addition, axonal transport of BACE1, Rab5, Rab7, lysosomes and mitochondria were also reduced in these neurons. Interestingly, axonal transport of these organelles was also affected in ASYN-/- neurons, suggesting that ASYN plays an important role in maintaining normal axonal transport function. Therefore, selective impairment of trafficking and processing of APP by ASYN may act as a potential mechanism to induce pathological features of Alzheimer's disease (AD) in PD patients.

α-突触核蛋白(ASYN)基因的突变或三倍体可导致包括帕金森氏病(PD)、路易体痴呆(DLB)和多系统萎缩(MSA)在内的联核病。为了定义ASYN的轴突功能，我们使用了表达GFP-人ASYN(GFP-hASYN)转基因的突触核病转基因小鼠模型和ASYN基因敲除(ASYN-/-)小鼠模型。我们的结果表明，转基因小鼠原代神经元中GFP-hASYN的表达损害了APP的轴突运输和加工。此外，这些神经元的BACE1、Rab5、Rab7、溶酶体和线粒体的轴突运输也减少。有趣的是，这些细胞器的轴突运输也在ASYN-/-神经元中受到影响，这表明ASYN在维持正常的轴突运输功能中起着重要作用。因此，ASYN对APP运输和加工的选择性损伤可能是诱发帕金森病患者阿尔茨海默病(AD)病理特征的潜在机制。

REF: Lin S, Leitão ADG, Fang S, et al. Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy. Neurobiol Dis. 2023;178:106010. doi:10.1016/j.nbd.2023.106010 PMID: 36702318

Role of NKCC1 and KCC2 during hypoxia-induced neuronal swelling in the neonatal neocortex

NKCC1和KCC2在缺氧诱导的新生大鼠新皮质神经元肿胀中的作用

Neonatal hypoxia causes cytotoxic neuronal swelling by the entry of ions and water. Multiple water pathways have been implicated in neurons because these cells lack water channels, and their membrane has a low water permeability. NKCC1 and KCC2 are cation-chloride cotransporters (CCCs) involved in water movement in various cell types. However, the role of CCCs in water movement in neonatal neurons during hypoxia is unknown. We studied the effects of modulating CCCs pharmacologically on neuronal swelling in the neocortex (layer IV/V) of neonatal mice (post-natal day 8-13) during prolonged and brief hypoxia.

新生儿缺氧通过离子和水的进入导致细胞毒性神经元肿胀。神经元中存在多条水通道，因为这些细胞缺乏水通道，其细胞膜具有低的水通透性。NKCC1和KCC2是阳离子-氯离子共转运体(CCCS)，参与不同类型细胞中的水分运动。然而，CCCS在缺氧时新生神经元水运动中的作用尚不清楚。我们从药理上研究了CCCS对新生小鼠(出生后第8-13天)新皮质(IV/V层)神经元在长时间和短暂缺氧过程中神经元肿胀的影响。

REF: Takezawa Y, Langton R, Baule SM, Zimmerman MB, Baek S, Glykys J. Role of NKCC1 and KCC2 during hypoxia-induced neuronal swelling in the neonatal neocortex. Neurobiol Dis. 2023;178:106013. doi:10.1016/j.nbd.2023.106013 PMID: 36706928