Acta Neuropathologica Communications最新文献

{"title":"Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.","authors":"Muhammad Ali, Derek B Archer, Priyanka Gorijala, Daniel Western, Jigyasha Timsina, Maria V Fernández, Ting-Chen Wang, Claudia L Satizabal, Qiong Yang, Alexa S Beiser, Ruiqi Wang, Gengsheng Chen, Brian Gordon, Tammie L S Benzinger, Chengjie Xiong, John C Morris, Randall J Bateman, Celeste M Karch, Eric McDade, Alison Goate, Sudha Seshadri, Richard P Mayeux, Reisa A Sperling, Rachel F Buckley, Keith A Johnson, Hong-Hee Won, Sang-Hyuk Jung, Hang-Rai Kim, Sang Won Seo, Hee Jin Kim, Elizabeth Mormino, Simon M Laws, Kang-Hsien Fan, M Ilyas Kamboh, Prashanthi Vemuri, Vijay K Ramanan, Hyun-Sik Yang, Allen Wenzel, Hema Sekhar Reddy Rajula, Aniket Mishra, Carole Dufouil, Stephanie Debette, Oscar L Lopez, Steven T DeKosky, Feifei Tao, Michael W Nagle, Timothy J Hohman, Yun Ju Sung, Logan Dumitrescu, Carlos Cruchaga","doi":"10.1186/s40478-023-01563-4","DOIUrl":"10.1186/s40478-023-01563-4","url":null,"abstract":"<p><p>Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10^-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10^-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10^-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10^-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10^-08, MAF = 0.006, sex-interaction P = 9.8 × 10^-07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10^-08, MAF = 0.004, sex-interaction P = 1.3 × 10^-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"68"},"PeriodicalIF":7.1,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10134547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10034447","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":"Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations.","authors":"Jessica Brown,&nbsp;Elena Camporesi,&nbsp;Juan Lantero-Rodriguez,&nbsp;Maria Olsson,&nbsp;Alice Wang,&nbsp;Blanca Medem,&nbsp;Henrik Zetterberg,&nbsp;Kaj Blennow,&nbsp;Thomas K Karikari,&nbsp;Mark Wall,&nbsp;Emily Hill","doi":"10.1186/s40478-023-01562-5","DOIUrl":"https://doi.org/10.1186/s40478-023-01562-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function, from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"67"},"PeriodicalIF":7.1,"publicationDate":"2023-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9811059","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":"Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation.","authors":"Marina Célestine,&nbsp;Muriel Jacquier-Sarlin,&nbsp;Eve Borel,&nbsp;Fanny Petit,&nbsp;Jean-Baptiste Perot,&nbsp;Anne-Sophie Hérard,&nbsp;Luc Bousset,&nbsp;Alain Buisson,&nbsp;Marc Dhenain","doi":"10.1186/s40478-023-01559-0","DOIUrl":"https://doi.org/10.1186/s40478-023-01559-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by intracerebral deposition of abnormal proteinaceous assemblies made of amyloid-β (Aß) peptides or tau proteins. These peptides and proteins induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aβ seeds from non-mutated Aβ_1-40 or Aβ_1-42 peptides can increase Aβ depositions several months after the infusion. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) that induce the production of Aβ peptides with different structures. The Aβ Osaka (Aβ_osa mutation (E693Δ)) is located within the Aβ sequence and thus the Aβ_osa peptides have different structures and properties as compared to non-mutated Aβ_1-42 peptides (Aβ_wt). Here, we wondered if a single exposure to this mutated Aβ can worsen AD pathology as well as downstream events including cognition, cerebral connectivity and synaptic health several months after the inoculation. To answer this question we inoculated Aβ_1-42-bearing Osaka mutation (Aβ_osa) in the dentate gyrus of APP_swe/PS1_dE9 mice at the age of two months. Their cognition and cerebral connectivity were analyzed at 4 months post-inoculation by behavioral evaluation and functional MRI. Aβ pathology as well as synaptic density were evaluated by histology. The impact of Aβ_osa peptides on synaptic health was also measured on primary cortical neurons. Remarkably, the intracerebral administration of Aβ_osa induced cognitive and synaptic impairments as well as a reduction of functional connectivity between different brain regions, 4 months post-inoculation. It increased Aβ plaque depositions and increased Aβ oligomers. This is the first study showing that a single, sporadic event as Aβ_osa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. It suggests that a single inoculation of Aβ regulates a large cascade of events for a long time.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"66"},"PeriodicalIF":7.1,"publicationDate":"2023-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9424796","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":"The locus coeruleus input to the rostral ventromedial medulla mediates stress-induced colorectal visceral pain.","authors":"Dexu Kong,&nbsp;Yunchun Zhang,&nbsp;Po Gao,&nbsp;Chao Pan,&nbsp;Haoyue Deng,&nbsp;Saihong Xu,&nbsp;Dan Tang,&nbsp;Jie Xiao,&nbsp;Yingfu Jiao,&nbsp;Weifeng Yu,&nbsp;Daxiang Wen","doi":"10.1186/s40478-023-01537-6","DOIUrl":"https://doi.org/10.1186/s40478-023-01537-6","url":null,"abstract":"<p><p>Unlike physiological stress, which carries survival value, pathological stress is widespread in modern society and acts as a main risk factor for visceral pain. As the main stress-responsive nucleus in the brain, the locus coeruleus (LC) has been previously shown to drive pain alleviation through direct descending projections to the spinal cord, but whether and how the LC mediates pathological stress-induced visceral pain remains unclear. Here, we identified a direct circuit projection from LC noradrenergic neurons to the rostral ventromedial medulla (RVM), an integral relay of the central descending pain modulation system. Furthermore, the chemogenetic activation of the LC-RVM circuit was found to significantly induce colorectal visceral hyperalgesia and anxiety-related psychiatric disorders in naïve mice. In a dextran sulfate sodium (DSS)-induced visceral pain model, the mice also presented colorectal visceral hypersensitivity and anxiety-related psychiatric disorders, which were associated with increased activity of the LC-RVM circuit; LC-RVM circuit inhibition markedly alleviated these symptoms. Furthermore, the chronic restraint stress (CRS) model precipitates anxiety-related psychiatric disorders and induces colorectal visceral hyperalgesia, which is referred to as pathological stress-induced hyperalgesia, and inhibiting the LC-RVM circuit attenuates the severity of colorectal visceral pain. Overall, the present study clearly demonstrated that the LC-RVM circuit could be critical for the comorbidity of colorectal visceral pain and stress-related psychiatric disorders. Both visceral inflammation and psychological stress can activate LC noradrenergic neurons, which promote the severity of colorectal visceral hyperalgesia through this LC-RVM circuit.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"65"},"PeriodicalIF":7.1,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9343545","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":"Tumor lineage-specific immune response in brain metastatic disease: opportunities for targeted immunotherapy regimen?","authors":"Shiva Najjary,&nbsp;Johan M Kros,&nbsp;Willem de Koning,&nbsp;Disha Vadgama,&nbsp;Karishma Lila,&nbsp;Janina Wolf,&nbsp;Dana A M Mustafa","doi":"10.1186/s40478-023-01542-9","DOIUrl":"https://doi.org/10.1186/s40478-023-01542-9","url":null,"abstract":"<p><p>Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found a more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45 + cells, T cells, and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3 + cells, and to fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"64"},"PeriodicalIF":7.1,"publicationDate":"2023-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9337453","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":"Movement disorders are linked to TDP-43 burden in the substantia nigra of FTLD-TDP brain donors.","authors":"Luigi Fiondella,&nbsp;Priya Gami-Patel,&nbsp;Christian A Blok,&nbsp;Annemieke J M Rozemuller,&nbsp;Jeroen J M Hoozemans,&nbsp;Yolande A L Pijnenburg,&nbsp;Marta Scarioni,&nbsp;Anke A Dijkstra","doi":"10.1186/s40478-023-01560-7","DOIUrl":"https://doi.org/10.1186/s40478-023-01560-7","url":null,"abstract":"<p><p>Movement disorders (MD) have been linked to degeneration of the substantia nigra (SN) in Parkinson's disease and include bradykinesia, rigidity, and tremor. They are also present in frontotemporal dementia (FTD), where MD have been linked to frontotemporal lobar degeneration with tau pathology (FTLD-tau). Although MD can also occur in FTLD with TDP-43 pathology (FTLD-TDP), the local pathology in the SN of FTLD-TDP patients with MD is currently unexplored. The aims of this study are to characterize the frequency and the nature of MD in a cohort of FTLD-TDP brain donors and to investigate the relationship between the presence of MD, the nigral neuronal loss, and the TDP-43 burden in the SN. From our cohort of FTLD-TDP patients (n = 53), we included 13 donors who presented with MD (FTLD-MD+), and nine age-sex matched donors without MD (FTLD-MD-) for whom the SN was available. In these donors, the TDP-43 burden and the neuronal density in the SN were assessed with ImageJ and Qupath software. The results were compared between the two groups using T-test. We found that the TDP-43 burden in the SN was higher in FTLD-MD+ (mean 3,43%, SD ± 2,7) compared to FTLD-MD- (mean 1,21%, SD ± 0,67) (p = 0,04), while no significant difference in nigral neuronal density was found between the groups (p = 0,09). 17% of FTLD-TDP patients developed MD, which present as symmetric akinetic-rigid parkinsonism or CBS. Given the absence of a significant nigral neuronal cell loss, TDP-43 induced neuronal dysfunction could be sufficient to cause MD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"63"},"PeriodicalIF":7.1,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10091586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9679014","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":"IGFBP2 promotes proliferation and cell migration through STAT3 signaling in Sonic hedgehog medulloblastoma.","authors":"Haritha Kunhiraman,&nbsp;Leon McSwain,&nbsp;Shubin W Shahab,&nbsp;Timothy R Gershon,&nbsp;Tobey J MacDonald,&nbsp;Anna Marie Kenney","doi":"10.1186/s40478-023-01557-2","DOIUrl":"https://doi.org/10.1186/s40478-023-01557-2","url":null,"abstract":"<p><p>Medulloblastoma (MB) is the most common pediatric brain malignancy and is divided into four molecularly distinct subgroups: WNT, Sonic Hedgehog (SHHp53mut and SHHp53wt), Group 3, and Group 4. Previous reports suggest that SHH MB features a unique tumor microenvironment compared with other MB groups. To better understand how SHH MB tumor cells interact with and potentially modify their microenvironment, we performed cytokine array analysis of culture media from freshly isolated MB patient tumor cells, spontaneous SHH MB mouse tumor cells and mouse and human MB cell lines. We found that the SHH MB cells produced elevated levels of IGFBP2 compared to non-SHH MBs. We confirmed these results using ELISA, western blotting, and immunofluorescence staining. IGFBP2 is a pleiotropic member of the IGFBP super-family with secreted and intracellular functions that can modulate tumor cell proliferation, metastasis, and drug resistance, but has been understudied in medulloblastoma. We found that IGFBP2 is required for SHH MB cell proliferation, colony formation, and cell migration, through promoting STAT3 activation and upregulation of epithelial to mesenchymal transition markers; indeed, ectopic STAT3 expression fully compensated for IGFBP2 knockdown in wound healing assays. Taken together, our findings reveal novel roles for IGFBP2 in SHH medulloblastoma growth and metastasis, which is associated with very poor prognosis, and they indicate an IGFBP2-STAT3 axis that could represent a novel therapeutic target in medulloblastoma.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"62"},"PeriodicalIF":7.1,"publicationDate":"2023-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9438140","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":"Exogenous interleukin 33 enhances the brain's lymphatic drainage and toxic protein clearance in acute traumatic brain injury mice.","authors":"Mingqi Liu,&nbsp;Jinhao Huang,&nbsp;Tao Liu,&nbsp;Jiangyuan Yuan,&nbsp;Chuanxiang Lv,&nbsp;Zhuang Sha,&nbsp;Chenrui Wu,&nbsp;Weiwei Jiang,&nbsp;Xuanhui Liu,&nbsp;Meng Nie,&nbsp;Yupeng Chen,&nbsp;Shiying Dong,&nbsp;Yu Qian,&nbsp;Chuang Gao,&nbsp;Yibing Fan,&nbsp;Di Wu,&nbsp;Rongcai Jiang","doi":"10.1186/s40478-023-01555-4","DOIUrl":"https://doi.org/10.1186/s40478-023-01555-4","url":null,"abstract":"<p><p>The persistent dysregulation and accumulation of poisonous proteins from destructive neural tissues and cells activate pathological mechanisms after traumatic brain injury (TBI). The lymphatic drainage system of the brain, composed of the glymphatic system and meningeal lymphatic vessels (MLVs), plays an essential role in the clearance of toxic waste after brain injury. The neuroprotective effect of interleukin 33 (IL-33) in TBI mice has been demonstrated; however, its impact on brain lymphatic drainage is unclear. Here, we established a fluid percussion injury model to examine the IL-33 administration effects on neurological function and lymphatic drainage in the acute brain of TBI mice. We verified that exogenous IL-33 could improve the motor and memory skills of TBI mice and demonstrated that in the acute phase, it increased the exchange of cerebrospinal and interstitial fluid, reversed the dysregulation and depolarization of aquaporin-4 in the cortex and hippocampus, improved the drainage of MLVs to deep cervical lymph nodes, and reduced tau accumulation and glial activation. We speculate that the protective effect of exogenous IL-33 on TBI mice's motor and cognitive functions is related to the enhancement of brain lymphatic drainage and toxic metabolite clearance from the cortex and hippocampus in the acute stage. These data further support the notion that IL-33 therapy may be an effective treatment strategy for alleviating acute brain injury after TBI.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"61"},"PeriodicalIF":7.1,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9275902","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":"Temporal tracking of microglial and monocyte single-cell transcriptomics in lethal flavivirus infection.","authors":"Alanna G Spiteri,&nbsp;Claire L Wishart,&nbsp;Duan Ni,&nbsp;Barney Viengkhou,&nbsp;Laurence Macia,&nbsp;Markus J Hofer,&nbsp;Nicholas J C King","doi":"10.1186/s40478-023-01547-4","DOIUrl":"https://doi.org/10.1186/s40478-023-01547-4","url":null,"abstract":"<p><p>As the resident parenchymal myeloid population in the central nervous system (CNS), microglia are strategically positioned to respond to neurotropic virus invasion and have been implicated in promoting both disease resolution and progression in the acute and post-infectious phase of virus encephalitis. In a mouse model of West Nile virus encephalitis (WNE), infection of the CNS results in recruitment of large numbers of peripheral immune cells into the brain, the majority being nitric oxide (NO)-producing Ly6C^hi inflammatory monocyte-derived cells (MCs). In this model, these cells enhance immunopathology and mortality. However, the contribution of microglia to this response is currently undefined. Here we used a combination of experimental tools, including single-cell RNA sequencing (scRNA-seq), microglia and MC depletion reagents, high-dimensional spectral cytometry and computational algorithms to dissect the differential contribution of microglia and MCs to the anti-viral immune response in severe neuroinflammation seen in WNE. Intriguingly, analysis of scRNA-seq data revealed 6 unique microglia and 3 unique MC clusters that were predominantly timepoint-specific, demonstrating substantial transcriptional adaptation with disease progression over the course of WNE. While microglia and MC adopted unique gene expression profiles, gene ontology enrichment analysis, coupled with microglia and MC depletion studies, demonstrated a role for both of these cells in the trafficking of peripheral immune cells into the CNS, T cell responses and viral clearance. Over the course of infection, microglia transitioned from a homeostatic to an anti-viral and then into an immune cell-recruiting phenotype. Conversely, MC adopted antigen-presenting, immune cell-recruiting and NO-producing phenotypes, which all had anti-viral function. Overall, this study defines for the first time the single-cell transcriptomic responses of microglia and MCs over the course of WNE, demonstrating both protective and pathological roles of these cells that could potentially be targeted for differential therapeutic intervention to dampen immune-mediated pathology, while maintaining viral clearance functions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"60"},"PeriodicalIF":7.1,"publicationDate":"2023-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9271016","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":"Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer's disease.","authors":"Kanza M Khan,&nbsp;Nagalakshmi Balasubramanian,&nbsp;Gabriel Gaudencio,&nbsp;Ruixiang Wang,&nbsp;Govindhasamy Pushpavathi Selvakumar,&nbsp;Louis Kolling,&nbsp;Samantha Pierson,&nbsp;Satya M Tadinada,&nbsp;Ted Abel,&nbsp;Marco Hefti,&nbsp;Catherine A Marcinkiewcz","doi":"10.1186/s40478-023-01546-5","DOIUrl":"https://doi.org/10.1186/s40478-023-01546-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in the brainstem, but a causal relationship has not been firmly established. This is due in part to a dearth of animal models that recapitulate early AD neuropathology and symptoms. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of AD that overexpresses human wild-type tau (htau) prior to the onset of cognitive impairments and assess these behavior changes in relationship to tau pathology, neuroinflammation, and monoaminergic dysregulation in the dorsal raphe nucleus (DRN) and locus coeruleus (LC). We observed depressive-like behaviors at 4 months in both sexes and hyperlocomotion in male htau mice. Deficits in social interaction persisted at 6 months and were accompanied by an increase in anxiety-like behavior in males. The behavioral changes at 4 months coincided with a lower density of serotonergic (5-HT) neurons, downregulation of 5-HT markers, reduced excitability of 5-HT neurons, and hyperphosphorylated tau in the DRN. Inflammatory markers were also upregulated in the DRN along with protein kinases and transglutaminase 2, which may promote tau phosphorylation and aggregation. Loss of 5-HT innervation to the entorhinal cortex and dentate gyrus of the hippocampus was also observed and may have contributed to depressive-like behaviors. There was also reduced expression of noradrenergic markers in the LC along with elevated phospho-tau expression, but this did not translate to a functional change in neuronal excitability. In total, these results suggest that tau pathology in brainstem monoaminergic nuclei and the resulting loss of serotonergic and/or noradrenergic drive may underpin depressive- and anxiety-like behaviors in the early stages of AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"11 1","pages":"57"},"PeriodicalIF":7.1,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9831032","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}