Neuropathology and Applied Neurobiology最新文献

{"title":"Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model.","authors":"Biao Cai, Nan Shao, Ting Ye, Peng Zhou, Wenwen Si, Hang Song, Guangyun Wang, 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, Yukiko Hata, Shojiro Ichimata, Koji Yoshida, 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}

{"title":"Past antihypertensive medication use is associated with lower levels of small vessel disease and lower Aβ plaque stage in the brains of older individuals.","authors":"Andrew J Affleck, Perminder S Sachdev, Glenda M Halliday","doi":"10.1111/nan.12922","DOIUrl":"10.1111/nan.12922","url":null,"abstract":"<p><strong>Aims: </strong>This study assesses the association of antihypertensive medication use on the severities of neuropathological cerebrovascular disease (CVD excluding lobar infarction) in older individuals.</p><p><strong>Methods: </strong>Clinical and neuropathological data were retrieved for 149 autopsy cases >75 years old with or without CVD or Alzheimer's disease and no other neuropathological diagnoses. Clinical data included hypertension status, hypertension diagnosis, antihypertensive medication use, antihypertensive medication dose (where available) and clinical dementia rating (CDR). Neuropathological CVD severity was evaluated for differences with anti-hypertensive medication usage.</p><p><strong>Results: </strong>Antihypertensive medication use was associated with less severe white matter small vessel disease (SVD, mainly perivascular dilatation and rarefaction), with a 5.6-14.4 times greater likelihood of less severe SVD if medicated. No significant relationship was detected between infarction (presence, type, number and size), lacunes or cerebral amyloid angiopathy and antihypertensive medication use. Only increased white matter rarefaction/oedema and not perivascular dilation was associated with Alzheimer's pathology, with a 4.3 times greater likelihood of reduced Aβ progression through the brain if white matter rarefaction severity was none or mild. Antihypertensive medication use was associated with reduced Aβ progression but only in those with moderate to severe white matter SVD.</p><p><strong>Conclusions: </strong>This histopathological study provides further evidence that antihypertensive medication use in older individuals is associated with white matter SVD and not with other CVD pathologies. This is mainly due to a reduction in white matter perivascular dilation and rarefaction/oedema. Even in those with moderate to severe white matter SVD, antihypertensive medication use reduced rarefaction and Aβ propagation through the brain.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12922"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10947144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10140257","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":"Beyond vacuolar pathology: Multiomic profiling of Danon disease reveals dysfunctional mitochondrial homeostasis.","authors":"Felix Kleefeld, Andreas Hentschel, Arpad von Moers, Katrin Hahn, Rita Horvath, Hans-Hilmar Goebel, Corinna Preusse, Jens Schallner, Markus Schuelke, Andreas Roos, Werner Stenzel","doi":"10.1111/nan.12920","DOIUrl":"10.1111/nan.12920","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12920"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195250","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":"Cover Image, Volume 49, Issue 4","authors":"Abrar Alhindi, Megan Shand, Hannah L. Smith, Ana S. Leite, Yu-Ting Huang, Dinja van der Hoorn, Zara Ridgway, K. Faller, Ross A. Jones, T. Gillingwater, Helena Chaytow","doi":"10.1111/nan.12930","DOIUrl":"https://doi.org/10.1111/nan.12930","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"1 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45471548","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":"First report of medulloblastoma in a patient with MUTYH-associated polyposis.","authors":"Marie-Charlotte Villy,&nbsp;Mathilde Warcoin,&nbsp;Mathilde Filser,&nbsp;Bruno Buecher,&nbsp;Lisa Golmard,&nbsp;Voreak Suybeng,&nbsp;Mathias Schwartz,&nbsp;Ivan Bieche,&nbsp;Sophie Vacher,&nbsp;Valérie Laurence,&nbsp;Franck Bourdeaut,&nbsp;Michèle Bernier,&nbsp;Tom Gutman,&nbsp;Dominique Stoppa-Lyonnet,&nbsp;Julien Masliah-Planchon,&nbsp;Chrystelle Colas","doi":"10.1111/nan.12929","DOIUrl":"https://doi.org/10.1111/nan.12929","url":null,"abstract":"<p><strong>Aims: </strong>The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.</p><p><strong>Methods: </strong>Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.</p><p><strong>Results: </strong>The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.</p><p><strong>Conclusions: </strong>Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12929"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10137368","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}