Translational Neurodegeneration最新文献

{"title":"Correction: A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau","authors":"Yang Gao, Yuying Wang, Huiyang Lei, Zhendong Xu, Shihong Li, Haitao Yu, Jiazhao Xie, Zhentao Zhang, Gongping Liu, Yao Zhang, Jie Zheng, Jian‑Zhi Wang","doi":"10.1186/s40035-024-00396-y","DOIUrl":"https://doi.org/10.1186/s40035-024-00396-y","url":null,"abstract":"<p><b>Correction</b>: <b>Translational Neurodegeneration 12:51 (2023)</b> <b>https://doi.org/10.1186/s40035-023-00379-5</b></p><p>Following publication of the original article [1], the authors reported an error in the Fig. 2:</p><p>Figure 2e presented a typing error \"HT7\" was wrongly written as \"HT1\". See the Fig. 2 corrected</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 2</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40035-024-00396-y/MediaObjects/40035_2024_396_Fig2_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"964\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40035-024-00396-y/MediaObjects/40035_2024_396_Fig2_HTML.png\" width=\"685\"/></picture><p>Increase of phosphorylated tau in the hippocampus of dox-administered hTau368 mice. <b>a</b> Diagram of human tau protein structure and phosphorylation epitopes measured in this study. <b>b</b>, <b>c</b> Dox treatment for 2 months showed no infuence on tau expression and phosphorylation in wild-type mice. Unpaired Student’s t-test, P > 0.05, n = 3 mice in each group. <b>d</b>, <b>e</b> Dox-treated hTau368 mice had higher levels of phosphorylated tau in the RIPA-soluble lysate of hippocampus. Homozygotes showed much more prominent pTau increase than hemizygotes. One-way ANOVA followed by Tukey’s multiple comparisons tests, *P < 0.05, **P < 0.01, ***P < 0.001, compared with the Veh group (n = 4 mice); <sup>#</sup>P < 0.05, Dox-Homo (n = 3 mice) compared with the Dox-Hemi group (n = 3 mice). <b>f</b>–<b>h</b> pTau aggregation in the hippocampus of Dox-treated hTau368 mice, detected by immunostaining for pS181, pS199 and AT8 tau. One-way ANOVA followed by Tukey’s multiple comparisons tests, ***P < 0.001, n = 3 mice in each group. <b>i</b>, <b>j</b> Dox-treated homozygous hTau368 mice had high levels of pTau in the RIPA-insoluble lysate of hippocampus. One-way ANOVA followed by Tukey’s multiple comparisons tests, *P < 0.05, compared with the Veh group, n = 3–4 mice in each group</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><p>The original article [1] has been corrected.</p><ol data-track-component=\"outbound reference\"><li data-counter=\"1.\"><p>Gao Y, Wang Y, Lei H, et al. A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau. Transl Neurodegener. 2023;12:51. https://doi.org/10.1186/s40035-023-00379-5.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><h3>Authors and Affiliations","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139423725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease.","authors":"Tao Zhang, Byeong Mo Kim, Tae Ho Lee","doi":"10.1186/s40035-023-00395-5","DOIUrl":"10.1186/s40035-023-00395-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson's disease (PD). We have established an upstream effect of DAPK1 on Aβ and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aβ deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"4"},"PeriodicalIF":12.6,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10775678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer’s disease","authors":"Xiu-Hong Qi, Peng Chen, Yue-Ju Wang, Zhe-Ping Zhou, Xue-Chun Liu, Hui Fang, Chen-Wei Wang, Ji Liu, Rong-Yu Liu, Han-Kui Liu, Zhen-Xin Zhang, Jiang-Ning Zhou","doi":"10.1186/s40035-023-00394-6","DOIUrl":"https://doi.org/10.1186/s40035-023-00394-6","url":null,"abstract":"Microglia-mediated neuroinflammation in Alzheimer’s disease (AD) is not only a response to pathophysiological events, but also plays a causative role in neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) is considered to be a stimulant for immune responses to diseases; however, it remains unknown whether CARS is involved in the pathogenesis of AD. Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining, real-time PCR, western blotting and ELISA. After that, C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation, as well as the underlying mechanisms. Finally, the associations of morphological features among CARS protein, microglia and dense-core plaques were examined by immunocytochemical staining. A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex. Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients. Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients. Moreover, overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice, respectively, accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines. In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells. The accumulation of CARS protein occurred within dense-core Aβ plaques accompanied by recruitment of ameboid microglia. Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD. The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits, which might be involved in the pathogenesis of AD.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"102 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139396574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology.","authors":"Hoda M Gebril, Aravind Aryasomayajula, Mariana Reis Nogueira de Lima, Kathryn E Uhrich, Prabhas V Moghe","doi":"10.1186/s40035-023-00393-7","DOIUrl":"10.1186/s40035-023-00393-7","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection.</p><p><strong>Methods: </strong>We designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM-NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM-NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines.</p><p><strong>Results: </strong>AM-NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ.</p><p><strong>Conclusions: </strong>The AM-NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"2"},"PeriodicalIF":12.6,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139088731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer’s disease","authors":"Min Zhang, Zhan Zhang, Honghong Li, Yuting Xia, Mengdan Xing, Chuan Xiao, Wenbao Cai, Lulu Bu, Yi Li, Tae-Eun Park, Yamei Tang, Xiaojing Ye, Wei-Jye Lin","doi":"10.1186/s40035-023-00388-4","DOIUrl":"https://doi.org/10.1186/s40035-023-00388-4","url":null,"abstract":"Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant type of dementia worldwide. It is characterized by the progressive and irreversible decline of cognitive functions. In addition to the pathological beta-amyloid (Aβ) deposition, glial activation, and neuronal injury in the postmortem brains of AD patients, increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology. Vascular endothelial growth factor (VEGF) plays a critical role in regulating physiological functions and pathological changes in blood vessels, but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear. We used an antiangiogenic agent for clinical cancer treatment, the humanized monoclonal anti-VEGF antibody bevacizumab, to block VEGF binding to its receptors in the 5×FAD mouse model at an early age. After treatment, memory performance was evaluated by a novel object recognition test, and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis. Immunofluorescence staining was used to measure glial activation and Aβ deposits. VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting. RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice. Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions, reduced glial activation, and restored long-term memory in both sexes of 5×FAD mice. Notably, a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice. Soluble VEGFR1 was decreased in female mice, while full-length VEGFR2 was increased in male mice. Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice. Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood–brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice. Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice. These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"20 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139082595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkinson’s disease and gut microbiota: from clinical to mechanistic and therapeutic studies","authors":"Xuxiang Zhang, Beisha Tang, Jifeng Guo","doi":"10.1186/s40035-023-00392-8","DOIUrl":"https://doi.org/10.1186/s40035-023-00392-8","url":null,"abstract":"Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases. The typical symptomatology of PD includes motor symptoms; however, a range of nonmotor symptoms, such as intestinal issues, usually occur before the motor symptoms. Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological, endocrine, and immune system pathways involved in the microbiota–gut–brain axis. In addition, extensive evidence suggests that the gut microbiota is strongly associated with PD. This review summarizes the latest findings on microbial changes in PD and their clinical relevance, describes the underlying mechanisms through which intestinal bacteria may mediate PD, and discusses the correlations between gut microbes and anti-PD drugs. In addition, this review outlines the status of research on microbial therapies for PD and the future directions of PD–gut microbiota research.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"22 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138686681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Supplementation with high-GABA-producing Lactobacillus plantarum L5 ameliorates essential tremor triggered by decreased gut bacteria-derived GABA","authors":"Hao-Jie Zhong, Si-Qi Wang, Ruo-Xin Zhang, Yu-Pei Zhuang, Longyan Li, Shuo-Zhao Yi, Ying Li, Lei Wu, Yu Ding, Jumei Zhang, Xinqiang Xie, Xing-Xiang He, Qingping Wu","doi":"10.1186/s40035-023-00391-9","DOIUrl":"https://doi.org/10.1186/s40035-023-00391-9","url":null,"abstract":"The γ-aminobutyric acid (GABA) hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor (ET). However, the specific causative factor for GABA deficiency is not clear. The gut microbiota in mammals has recently been considered as a significant source of GABA. Furthermore, the GABA-based signals originating from the intestine can be transmitted to the brain through the “enteric nervous system–vagus nerve–brain” axis. However, the plausible contribution of gut microbiota to ET seems inspiring but remains obscure. Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis. The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model. Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry. Subsequently, mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5. Tremor severity, behavioral tests, pro-inflammatory cytokines, GABA concentration, and gut microbiota composition were examined in these mice. The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration. Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET. L5 exhibited an augmented GABA-producing capacity, with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA. In addition, administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice. In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition, supplemented the mucosa-associated microbiota with GABA-producing capacity, increased the GABA concentrations in the cerebellum, and diminished inflammation in the central nervous system. These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138579233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel data-driven subtypes and stages of brain atrophy in the ALS–FTD spectrum","authors":"Ting Shen, Jacob W. Vogel, Jeffrey Duda, Jeffrey S. Phillips, Philip A. Cook, James Gee, Lauren Elman, Colin Quinn, Defne A. Amado, Michael Baer, Lauren Massimo, Murray Grossman, David J. Irwin, Corey T. McMillan","doi":"10.1186/s40035-023-00389-3","DOIUrl":"https://doi.org/10.1186/s40035-023-00389-3","url":null,"abstract":"TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS–FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS–FTD spectrum. We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS–FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS–FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease. SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS–FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King’s stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology. Our findings suggest distinct neurodegenerative subtypes of disease along the ALS–FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138547102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model.","authors":"Carolyn Tallon, Benjamin J Bell, Medhinee M Malvankar, Pragney Deme, Carlos Nogueras-Ortiz, Erden Eren, Ajit G Thomas, Kristen R Hollinger, Arindom Pal, Maja Mustapic, Meixiang Huang, Kaleem Coleman, Tawnjerae R Joe, Rana Rais, Norman J Haughey, Dimitrios Kapogiannis, Barbara S Slusher","doi":"10.1186/s40035-023-00383-9","DOIUrl":"10.1186/s40035-023-00383-9","url":null,"abstract":"<p><strong>Background: </strong>Cognitive decline in Alzheimer's disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity.</p><p><strong>Methods: </strong>To determine the therapeutic benefit of inhibiting this elevation, we evaluated PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model. Additionally, we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus (AAV) encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus. The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored. We examined ceramide levels, histopathological changes, and pTau content within EVs isolated from the mouse plasma.</p><p><strong>Results: </strong>Similar to human AD, the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity; both were completely normalized by PDDC treatment. The PS19 mice also exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all of which were pathologic features of human AD. PDDC treatment reduced these changes. The plasma of PDDC-treated PS19 mice had reduced levels of neuronal- and microglial-derived EVs, the former carrying lower pTau levels, compared to untreated mice. In the tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.</p><p><strong>Conclusions: </strong>PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity, leading to the slowing of tau spread in AD mice.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"56"},"PeriodicalIF":12.6,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10694940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138483028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal and synaptic adaptations underlying the benefits of deep brain stimulation for Parkinson's disease.","authors":"Wenying Xu, Jie Wang, Xin-Ni Li, Jingxue Liang, Lu Song, Yi Wu, Zhenguo Liu, Bomin Sun, Wei-Guang Li","doi":"10.1186/s40035-023-00390-w","DOIUrl":"10.1186/s40035-023-00390-w","url":null,"abstract":"<p><p>Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides a unique approach that allows cell type- and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment. DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons. This orchestration leads to conversion of firing patterns, enabling both antidromic and orthodromic modulation of neural circuits. Understanding these mechanisms is vital for decoding position- and programming-dependent effects of DBS. Furthermore, patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits. Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns. Advanced technologies, such as adaptive DBS or directional electrodes, can also be integrated for circuit-specific neuromodulation. These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":"55"},"PeriodicalIF":12.6,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10688037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138462862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}