Neuropathology and Applied Neurobiology最新文献

{"title":"Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies.","authors":"Julie Lerond,&nbsp;Bertrand Mathon,&nbsp;Mélina Scopin,&nbsp;Lucia Nichelli,&nbsp;Justine Guégan,&nbsp;Céline Bertholle,&nbsp;Brigitte Izac,&nbsp;Muriel Andrieu,&nbsp;Thomas Gareau,&nbsp;Florian Donneger,&nbsp;Badreddine Mohand Oumoussa,&nbsp;Franck Letourneur,&nbsp;Suzanne Tran,&nbsp;Mathilde Bertrand,&nbsp;Isabelle Le Roux,&nbsp;Mehdi Touat,&nbsp;Sophie Dupont,&nbsp;Jean Christophe Poncer,&nbsp;Vincent Navarro,&nbsp;Franck Bielle","doi":"10.1111/nan.12937","DOIUrl":"10.1111/nan.12937","url":null,"abstract":"<p><strong>Objective: </strong>Mesial Temporal Lobe Epilepsy-associated Hippocampal Sclerosis (MTLE-HS) is a syndrome associated with various aetiologies. We previously identified CD34-positive extravascular stellate cells (CD34+ cells) possibly related to BRAF^V600E oncogenic variant in a subset of MTLE-HS. We aimed to identify the BRAF^V600E oncogenic variants and characterise the CD34+ cells.</p><p><strong>Methods: </strong>We analysed BRAF^V600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE-HS samples (25 with CD34+ cells) and nine non-expansive neocortical lesions resected during epilepsy surgery (five with CD34+ cells). Ex vivo multi-electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAF^wildtype MTLE-HS and BRAF^V600E mutant non-expansive lesion of hippocampus and/or neocortex.</p><p><strong>Results: </strong>We identified a BRAF^V600E oncogenic variant in five MTLE-HS samples with CD34+ cells (19%) and in five neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAF^V600E mutant samples. The co-expression of the oncogene-induced senescence marker p16^INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in eight of the 10 patients with BRAF mutant lesions.</p><p><strong>Interpretation: </strong>BRAF^V600E underlies a subset of MTLE-HS and epileptogenic non-expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and open perspectives for targeted therapies.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":" ","pages":"e12937"},"PeriodicalIF":5.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41159400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cu^II(atsm) significantly decreases microglial reactivity in patients with sporadic amyotrophic lateral sclerosis.","authors":"Jeffrey R Liddell, James B W Hilton, Peter J Crouch","doi":"10.1111/nan.12938","DOIUrl":"10.1111/nan.12938","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 5","pages":"e12938"},"PeriodicalIF":5.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis?","authors":"Katja Thümmler,&nbsp;Claudia Wrzos,&nbsp;Jonas Franz,&nbsp;Daniel McElroy,&nbsp;John J Cole,&nbsp;Lorna Hayden,&nbsp;Diana Arseni,&nbsp;Friedrich Schwarz,&nbsp;Andreas Junker,&nbsp;Julia M Edgar,&nbsp;Sebastian Kügler,&nbsp;Andreas Neef,&nbsp;Fred Wolf,&nbsp;Christine Stadelmann,&nbsp;Christopher Linington","doi":"10.1111/nan.12935","DOIUrl":"10.1111/nan.12935","url":null,"abstract":"<p><strong>Aims: </strong>Fibroblast growth factor (FGF) signalling is dysregulated in multiple sclerosis (MS) and other neurological and psychiatric conditions, but there is little or no consensus as to how individual FGF family members contribute to disease pathogenesis. Lesion development in MS is associated with increased expression of FGF1, FGF2 and FGF9, all of which modulate remyelination in a variety of experimental settings. However, FGF9 is also selectively upregulated in major depressive disorder (MDD), prompting us to speculate it may also have a direct effect on neuronal function and survival.</p><p><strong>Methods: </strong>Transcriptional profiling of myelinating cultures treated with FGF1, FGF2 or FGF9 was performed, and the effects of FGF9 on cortical neurons investigated using a combination of transcriptional, electrophysiological and immunofluorescence microscopic techniques. The in vivo effects of FGF9 were explored by stereotactic injection of adeno-associated viral (AAV) vectors encoding either FGF9 or EGFP into the rat motor cortex.</p><p><strong>Results: </strong>Transcriptional profiling of myelinating cultures after FGF9 treatment revealed a distinct neuronal response with a pronounced downregulation of gene networks associated with axonal transport and synaptic function. In cortical neuronal cultures, FGF9 also rapidly downregulated expression of genes associated with synaptic function. This was associated with a complete block in the development of photo-inducible spiking activity, as demonstrated using multi-electrode recordings of channel rhodopsin-transfected rat cortical neurons in vitro and, ultimately, neuronal cell death. Overexpression of FGF9 in vivo resulted in rapid loss of neurons and subsequent development of chronic grey matter lesions with neuroaxonal reduction and ensuing myelin loss.</p><p><strong>Conclusions: </strong>These observations identify overexpression of FGF9 as a mechanism by which neuroaxonal pathology could develop independently of immune-mediated demyelination in MS. We suggest targeting neuronal FGF9-dependent pathways may provide a novel strategy to slow if not halt neuroaxonal atrophy and loss in MS, MDD and potentially other neurodegenerative diseases.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":" ","pages":"e12935"},"PeriodicalIF":5.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10233348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain pathology of lissencephaly type 2 with an ISPD pathogenic variant.","authors":"Julia Keith,&nbsp;Patrick Shannon","doi":"10.1111/nan.12939","DOIUrl":"10.1111/nan.12939","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":" ","pages":"e12939"},"PeriodicalIF":5.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41145048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model.","authors":"Biao Cai,&nbsp;Nan Shao,&nbsp;Ting Ye,&nbsp;Peng Zhou,&nbsp;Wenwen Si,&nbsp;Hang Song,&nbsp;Guangyun Wang,&nbsp;Junping Kou","doi":"10.1111/nan.12934","DOIUrl":"10.1111/nan.12934","url":null,"abstract":"Hyperphosphorylation of Tau is one of the important pathological features of Alzheimer's disease (AD). Therefore, studying the mechanisms behind Tau hyperphosphorylation is crucial in exploring the pathogenesis of neurological damage in AD.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":" ","pages":"e12934"},"PeriodicalIF":5.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10580354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An autopsy case of late-onset spinocerebellar atrophy type 14.","authors":"Kyoka Ogawa,&nbsp;Yukiko Hata,&nbsp;Shojiro Ichimata,&nbsp;Koji Yoshida,&nbsp;Naoki Nishida","doi":"10.1111/nan.12936","DOIUrl":"10.1111/nan.12936","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":" ","pages":"e12936"},"PeriodicalIF":5.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10598214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the pathological basis of dementia from population-based neuropathology studies.","authors":"Stephen B Wharton, Julie E Simpson, Paul G Ince, Connor D Richardson, Richard Merrick, Fiona E Matthews, Carol Brayne","doi":"10.1111/nan.12923","DOIUrl":"10.1111/nan.12923","url":null,"abstract":"<p><p>The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case-control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age-related TDP-43 encephalopathy, ageing-related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12923"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoscale reorganisation of synaptic proteins in Alzheimer's disease.","authors":"Wang-Hui Zhu,&nbsp;Xiao-Xu Yang,&nbsp;Xu-Zhuo Gou,&nbsp;Shu-Mei Fu,&nbsp;Jia-Hui Chen,&nbsp;Feng Gao,&nbsp;Yong Shen,&nbsp;Dan-Lei Bi,&nbsp;Ai-Hui Tang","doi":"10.1111/nan.12924","DOIUrl":"https://doi.org/10.1111/nan.12924","url":null,"abstract":"<p><strong>Aims: </strong>Synaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano-organisation is altered in AD. Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD.</p><p><strong>Methods: </strong>We used immunostaining and super-resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano-organisation in both Aβ1-42-treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice.</p><p><strong>Results: </strong>We found that Aβ1-42-treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild-type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release-guiding RIM1/2 and postsynaptic scaffolding protein PSD-95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aβ plaques with dense cores.</p><p><strong>Conclusions: </strong>Our study revealed a spatiotemporal-specific reorganisation of synaptic nanostructures in AD and identifies dense-core amyloid plaques as the major local inductor in APP23 mice.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12924"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"microRNA-based predictor for diagnosis of frontotemporal dementia.","authors":"Iddo Magen, Nancy-Sarah Yacovzada, Jason D Warren, Carolin Heller, Imogen Swift, Yoana Bobeva, Andrea Malaspina, Jonathan D Rohrer, Pietro Fratta, Eran Hornstein","doi":"10.1111/nan.12916","DOIUrl":"10.1111/nan.12916","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to explore the non-linear relationships between cell-free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis.</p><p><strong>Methods: </strong>We initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls).</p><p><strong>Results: </strong>On the basis of cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non-linear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ~90% of cases.</p><p><strong>Conclusions: </strong>The fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12916"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis.","authors":"Abrar Alhindi,&nbsp;Megan Shand,&nbsp;Hannah L Smith,&nbsp;Ana S Leite,&nbsp;Yu-Ting Huang,&nbsp;Dinja van der Hoorn,&nbsp;Zara Ridgway,&nbsp;Kiterie M E Faller,&nbsp;Ross A Jones,&nbsp;Thomas H Gillingwater,&nbsp;Helena Chaytow","doi":"10.1111/nan.12925","DOIUrl":"https://doi.org/10.1111/nan.12925","url":null,"abstract":"<p><strong>Aims: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying-back' pathology in models of SOD1-dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP-43, a key mediator protein in ALS, is overexpressed in neurons in Thy1-hTDP-43^WT mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS.</p><p><strong>Methods: </strong>Expression of TDP-43 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ-morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology.</p><p><strong>Results: </strong>We present a time course of progressive, region-specific motor neuron pathology in Thy1-hTDP-43^WT mice. Thy1-driven hTDP-43 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21 days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status.</p><p><strong>Conclusions: </strong>Thy1-hTDP-43^WT mice represent a severe model of ALS, with NMJ pathology/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying-back pathology, as well as NMJ-targeting disease-modifying therapies in ALS.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12925"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}