ACTA NEUROPATHOLOGICA COMMUNICATIONS (ANC) 在提交后的两个月内使用分子、细胞和形态学技术发表基于实验或人体组织的神经疾病机制的文章。

The journal Acta neuropathologica communications (ANC) aims to publish articles on the mechanisms of neurological diseases based on experimental or human tissue within two months of submission, utilizing molecular, cellular, and morphological techniques.

《Acta neuropathologica communications》（ANC）期刊致力于在提交后的两个月内，利用分子、细胞和形态学技术，发表关于神经疾病机制的研究文章，这些研究基于实验或人体组织。

Acta neuropathologica communications

Axonal dystrophies (AxDs) are swollen and tortuous neuronal processes that are associated with extracellular depositions of amyloid β (Aβ) and have been observed to contribute to synaptic alterations occurring in Alzheimer's disease. Understanding the temporal course of this axonal pathology is of high relevance to comprehend the progression of the disease over time. We performed a long-term in vivo study (up to 210 days of two-photon imaging) with two transgenic mouse models (dE9xGFP-M and APP-PS1xGFP-M). Interestingly, AxDs were formed only in a quarter of GFP-expressing axons near Aβ-plaques, which indicates a selective vulnerability. AxDs, especially those reaching larger sizes, had long lifetimes and appeared as highly plastic structures with large variations in size and shape and axonal sprouting over time. In the case of the APP-PS1 mouse only, the formation of new long axonal segments in dystrophic axons (re-growth phenomenon) was observed. Moreover, new AxDs could appear at the same point of the axon where a previous AxD had been located before disappearance (re-formation phenomenon). In addition, we observed that most AxDs were formed and developed during the imaging period, and numerous AxDs had already disappeared by the end of this time. This work is the first in vivo study analyzing quantitatively the high plasticity of the axonal pathology around Aβ plaques. We hypothesized that a therapeutically early prevention of Aβ plaque formation or their growth might halt disease progression and promote functional axon regeneration and the recovery of neural circuits.

Lidia Blazquez-Llorca

Susana Valero-Freitag

Eva Ferreira Rodrigues

Ángel Merchán-Pérez

J. Rodrigo Rodríguez

Mario M. Dorostkar

Javier DeFelipe

Jochen Herms

Acta Neuropathologica Communications

High plasticity of axonal pathology in Alzheimer’s disease mouse models

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.

Eva Martin-Solana

Laura Casado-Zueras

Teobaldo E. Torres

Gerardo F. Goya

Maria-Rosario Fernandez-Fernandez

Jose-Jesus Fernandez

Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy

In Alzheimer's disease (AD) a variety of amyloid β-peptides (Aβ) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of Aβ from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by β- and γ-secretases. Brain accumulation of Aβ due to impaired Aβ degradation and/or altered ratios between the different Aβ species produced is believed to play a pivotal role in AD pathogenesis. While the presence of Aβ40 and Aβ42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated Aβ peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of Aβ37 and Aβ39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 ΔExon9 mutation. Aβ37 and Aβ39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of Aβ37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated Aβ in sporadic and familial AD and raises questions about how these species are generated and regulated.

Jochim Reinert

Bernhard C. Richard

Hans W. Klafki

Beate Friedrich

Thomas A. Bayer

Jens Wiltfang

Gabor G. Kovacs

Martin Ingelsson

Lars Lannfelt

Anders Paetau

Jonas Bergquist

Oliver Wirths

Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer’s disease and transgenic mouse models

阿尔茨海默病及转基因小鼠模型中C端截短的Aβ物种Aβ37和Aβ39的沉积

Abstract Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. SARM1 protein is a central driver of axon degeneration through a conserved molecular pathway. Sarm1 −/− mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of the SARM1 pathway as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classification of pathology of individual axons, using electron microscopy, demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. Longitudinal MRI studies in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited beneficial effects in motor learning and sleep behavior. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.

Donald V. Bradshaw

Andrew K. Knutsen

Alexandru Korotcov

Genevieve M. Sullivan

Kryslaine L. Radomski

Bernard J. Dardzinski

Xiaomei Zi

Dennis P. McDaniel

Regina C. Armstrong

Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

基于病理学、放射学和功能性指标的实验性创伤性脑损伤后SARM1轴突退变途径的基因失活改善了结果轨迹

Craniopharyngiomas (CP) are rare epithelial tumors of the sellar region. Two subtypes, adamantinomatous (adaCP) and papillary CP (papCP), were previously identified based on histomorphological and epidemiological aspects. Recent data indicates that both variants are defined by specific genetic alterations, and influenced by distinct molecular pathways and particular origins. The fact that CP is an uncommon tumor entity renders studies on large cohorts difficult and exceptional. In order to achieve further insights distinguishing CP variants, we conducted whole genome methylation (450 k array) and microarray-based gene expression studies in addition to CTNNB1 and BRAF mutation analysis using a comprehensive cohort of 80 adaCP and 35 papCP. BRAF V600E mutations were solely found in the papCP subgroup and were not detectable in adaCP samples. In contrast, CTNNB1 mutations were exclusively detected in adaCP. The methylome fingerprints assigned DNA specimens to entity-specific groups (papCP (n = 18); adaCP (n = 25)) matching perfectly with histology-based diagnosis, suggesting that they represent truly distinct biological entities. However, we were not able to detect within the adaCP group (including 11 pediatric and 14 adult cases) a significant difference in methylation signature by age. Integrative comparison of the papCP with the adaCP group based on differential gene expression and methylation revealed a distinct upregulation of Wnt- and SHH signaling pathway genes in adaCP. AdaCP and papCP thus represent distinct tumor subtypes that harbor mutually exclusive gene mutations and methylation patterns, further reflected in differences in gene expression. This study demonstrates that DNA methylation analyses are an additional method to classify CP into subtypes, and implicates a role of epigenetic mechanisms in the genesis of the respective CP variants. Detection of tumor-specific signaling pathway activation enables the possibility of target-oriented intervention.

Annett Hölsken

Martin Sill

Jessica Merkle

Leonille Schweizer

Michael Buchfelder

Jörg Flitsch

Rudolf Fahlbusch

Markus Metzler

Marcel Kool

Stefan M. Pfister

Andreas von Deimling

David Capper

David T. W. Jones

Rolf Buslei

acta neuropathol commun

Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles

成釉细胞型和乳头型颅咽管瘤具有独特的表观基因组特征以及突变和转录组特征

Xi-Biao He

Fang Guo

Wei Zhang

Jiacheng Fan

Weidong Le

Qi Chen

Yongjun Ma

Yong Zheng

Sang-Hun Lee

Hui-Jing Wang

Yi Wu

Qinming Zhou

Rui Yang

JMJD3 deficiency disturbs dopamine biosynthesis in midbrain and aggravates chronic inflammatory pain

JMJD3缺乏扰乱中脑多巴胺生物合成并加剧慢性炎症性疼痛

Abstract Severity and outcome of strokes following cerebral hypoperfusion are significantly influenced by stress responses of the blood vessels. In this context, brain endothelial cells (BEC) regulate inflammation, angiogenesis and the vascular resistance to rapidly restore perfusion. Despite the relevance of these responses for infarct volume and tissue recovery, their transcriptional control in BEC is not well characterized. We revealed that oxygen and nutrient-deprived BEC activate nuclear factor of activated T-cells 5 (NFAT5)—a transcription factor that adjusts the cellular transcriptome to cope with environmental stressors. We hypothesized that NFAT5 controls the expression of genes regulating the response of BEC in the ischemic brain. The functional relevance of NFAT5 was assessed in mice, allowing the conditional EC-specific knock-out of Nfat5 ( Nfat5 (EC)−/− ). Cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) followed reperfusion up to 28 days. While loss of endothelial Nfat5 did not evoke any phenotypic abnormalities in mice under control conditions, infarct volumes, neurological deficits and the degree of brain atrophy were significantly pronounced following MCAO as compared to control animals ( Nfat5 fl/fl ). In contrast, MCAO-induced edema formation, inflammatory processes and angiogenesis were not altered in Nfat5 (EC)−/− mice. RNAseq analyses of cultured BEC suggested that loss of NFAT5 impairs the expression of Kcnj2 encoding a potassium channel that may affect reperfusion. In fact, lower levels of KCNJ2 were detected in arterial endothelial cells of Nfat5 (EC)−/− versus Nfat5 fl/fl mice. Laser speckle contrast imaging of the brain revealed an impaired perfusion recovery in Nfat5 (EC)−/− versus Nfat5 fl/fl mice after MCAO.Collectively, NFAT5 in arterial BEC is required for an adequate reperfusion response after brain ischemia that is presumably dependent on the maintenance of Kcnj2 expression. Consequently, impairment of the protective role of endothelial NFAT5 results in enlarged infarct sizes and more severe functional deficits of brain functions.

Reiner Kunze

Paul Wacker

Paula Breuer

Emil Nasyrov

Ivan M. Kur

Andreas Weigert

Andreas H. Wagner

Hugo H. Marti

Thomas Korff

Adequate post-ischemic reperfusion of the mouse brain requires endothelial NFAT5

小鼠脑缺血后充分再灌注需要内皮NFAT5

Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD.

Aya Jishi

Di Hu

Yutong Shang

Rihua Wang

Steven A. Gunzler

Xin Qi

BCKDK loss impairs mitochondrial Complex I activity and drives alpha-synuclein aggregation in models of Parkinson’s disease

BCKDK缺乏损害线粒体复合物I活性并驱动帕金森病模型中α-突触核蛋白聚集

Abstract Alterations to the composition and function of neuronal nuclear pore complexes (NPCs) have been documented in multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Moreover, recent work has suggested that injury to the NPC can at least in part contribute to TDP-43 loss of function and mislocalization, a pathological hallmark of ALS and related neurodegenerative diseases. Collectively, these studies highlight a role for disruptions in NPC homeostasis and surveillance as a significant pathophysiologic event in neurodegeneration. The ESCRT-III nuclear surveillance pathway plays a critical role in the surveillance and maintenance of NPCs and the surrounding nuclear environment. Importantly, pathologic alterations to this pathway and its protein constituents have been implicated in neurodegenerative diseases such as ALS. However, the mechanism by which this pathway contributes to disease associated alterations in the NPC remains unknown. Here we use an induced pluripotent stem cell (iPSC) derived neuron (iPSN) model of sALS to demonstrate that CHMP7/ESCRT-III nuclear maintenance/surveillance is overactivated in sALS neurons. This overactivation is dependent upon the ESCRT-III protein CHMP2B and sustained CHMP2B dependent “activation” is sufficient to contribute to pathologic CHMP7 nuclear accumulation and POM121 reduction. Importantly, partial knockdown of CHMP2B was sufficient to alleviate NPC injury and downstream TDP-43 dysfunction in sALS neurons thereby highlighting CHMP2B as a potential therapeutic target in disease.

Olivia Keeley

Emma Mendoza

Druv Menon

Alyssa N. Coyne

CHMP2B promotes CHMP7 mediated nuclear pore complex injury in sporadic ALS

CHMP2B促进CHMP7介导的散发性ALS中核孔复合体损伤

Abstract Evidence that myelin repair is crucial for functional recovery in multiple sclerosis (MS) led to the identification of bexarotene (BXT). This clinically promising remyelinating agent activates multiple nuclear hormone receptor subtypes implicated in myelin repair. However, BXT produces unacceptable hyperlipidemia. In contrast, IRX4204 selectively activates the retinoid X receptor (RXR). Given compelling links between RXR activation and increased myelin repair, we employed IRX4204 to investigate the impact of RXR agonism alone on functional recovery in mice subjected to experimental autoimmune encephalomyelitis (EAE). Since gait deficits are common in MS, we used machine learning to obtain highly sensitive and reliable measurements of sagittal hindleg joint movements for mice walking on a treadmill. IRX4204 not only blocked the progressive loss of knee and ankle movements but also reversed joint movement impairments in EAE mice. Our biochemical, transcriptional and histological measurements in spinal cord suggest these gait improvements reflect increased axon survival and remyelination and reduced inflammation. Using microglia, astrocytes and oligodendrocyte progenitor cells, we present additional data suggesting that IRX4204 may act on multiple glial subtypes to orchestrate myelin repair. These results inform the discovery of restorative neural therapeutics for MS by demonstrating that selective RXR agonism is sufficient for effective myelin repair. Moreover, our findings support the therapeutic potential of IRX4204 to promote functional recovery in MS.

Gracious D. S. Kasheke

Basmah A. M. Hendy

Gabriel G. Dorighello

Nonthué A. Uccelli

Jean-David M. Gothié

Robyn J. Novorolsky

Madison J. Oulton

Jude Asainayagam

Adam I. Makarov

Kaitlyn S. Fraser

Vidyasagar Vuligonda

Martin E. Sanders

Timothy E. Kennedy

George S. Robertson

Selective retinoid X receptor agonism promotes functional recovery and myelin repair in experimental autoimmune encephalomyelitis

选择性维甲酸X受体激动剂促进实验性自身免疫性脑脊髓炎的功能恢复和髓鞘修复

Abbreviation	Acta Neuropathol. Commun.
Journal Impact	6.29
Quartiles(Global)	NEUROSCIENCES(Q1)

ISSN	2051-5960
h-index	87
Top Journals	Yes

Publication Information	Publisher: BioMed Central Ltd，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2013，Proportion of original research papers: 94.89%，Self Citation Rate:3.20%， Gold OA Rate: 100.00%
Journal Fees	$3590Details
Average review cycle	网友分享经验：8 Weeks

Acta neuropathologica communications

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