Molecular Neurodegeneration最新文献

{"title":"Fluid biomarkers for amyotrophic lateral sclerosis: a review","authors":"Katherine E. Irwin, Udit Sheth, Philip C. Wong, Tania F. Gendron","doi":"10.1186/s13024-023-00685-6","DOIUrl":"https://doi.org/10.1186/s13024-023-00685-6","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"10 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139544240","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":"Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD","authors":"Bilal Khalil, Miriam Linsenmeier, Courtney L. Smith, James Shorter, Wilfried Rossoll","doi":"10.1186/s13024-023-00698-1","DOIUrl":"https://doi.org/10.1186/s13024-023-00698-1","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function. Here, we showcase the NIR family and how they recognize cargo, drive nuclear import, and chaperone prion-like RBPs linked to ALS/FTD. We also discuss the promise of enhancing NIR levels and developing potentiated NIR variants as therapeutic strategies for ALS/FTD and related neurodegenerative proteinopathies. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"33 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139510848","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":"Unravelling cell type-specific responses to Parkinson’s Disease at single cell resolution","authors":"Araks Martirosyan, Rizwan Ansari, Francisco Pestana, Katja Hebestreit, Hayk Gasparyan, Razmik Aleksanyan, Silvia Hnatova, Suresh Poovathingal, Catherine Marneffe, Dietmar R. Thal, Andrew Kottick, Victor J. Hanson-Smith, Sebastian Guelfi, William Plumbly, T. Grant Belgard, Emmanouil Metzakopian, Matthew G. Holt","doi":"10.1186/s13024-023-00699-0","DOIUrl":"https://doi.org/10.1186/s13024-023-00699-0","url":null,"abstract":"Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson’s Disease (PD) cases and 14 Controls. Our dataset comprises ∼84K nuclei, representing all major cell types of the brain, allowing us to obtain a transcriptome-level characterization of these cell types. Importantly, we identify multiple subpopulations for each cell type and describe specific gene sets that provide insights into the differing roles of these subpopulations. Our findings reveal a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrate a significant depletion of tyrosine hydroxylase (TH) enriched astrocyte, microglia and oligodendrocyte populations in PD samples, as well as TH enriched neurons, which are also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes, including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"128 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139504928","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":"Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer's disease.","authors":"Maria Calvo-Rodriguez, Elizabeth K Kharitonova, Austin C Snyder, Steven S Hou, Maria Virtudes Sanchez-Mico, Sudeshna Das, Zhanyun Fan, Hamid Shirani, K Peter R Nilsson, Alberto Serrano-Pozo, Brian J Bacskai","doi":"10.1186/s13024-024-00702-2","DOIUrl":"10.1186/s13024-024-00702-2","url":null,"abstract":"<p><strong>Background: </strong>Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.</p><p><strong>Methods: </strong>We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques.</p><p><strong>Results: </strong>For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden.</p><p><strong>Conclusions: </strong>Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"6"},"PeriodicalIF":14.9,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10797952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139491673","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":"Brain clearance of protein aggregates: a close-up on astrocytes","authors":"Veronica Giusti, Gurkirat Kaur, Elena Giusto, Laura Civiero","doi":"10.1186/s13024-024-00703-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00703-1","url":null,"abstract":"Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts. Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process. However, the molecular mechanisms used by astrocytes to remove misfolded proteins are still largely unknown. Here we first provide a brief overview of the progressive transition from soluble monomers to insoluble fibrils that characterizes amyloid proteins, referring to α-Synuclein and Tau as archetypical examples. We then highlight the mechanisms at the basis of astrocyte-mediated clearance with a focus on their potential ability to recognize, collect, internalize and digest extracellular protein aggregates. Finally, we explore the potential of targeting astrocyte-mediated clearance as a future therapeutic approach for the treatment of neurodegenerative disorders characterized by protein misfolding and accumulation.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"56 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139474285","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":"Neuronal and glial vulnerability of the suprachiasmatic nucleus in tauopathies: evidence from human studies and animal models.","authors":"Gowoon Son, Thomas C Neylan, Lea T Grinberg","doi":"10.1186/s13024-023-00695-4","DOIUrl":"10.1186/s13024-023-00695-4","url":null,"abstract":"<p><p>Tauopathies, a group of neurodegenerative diseases that includes Alzheimer's disease, commonly lead to disturbances in sleep-wake patterns and circadian rhythm disorders. The circadian rhythm, a recurring 24-hour cycle governing human biological activity, is regulated by the hypothalamic suprachiasmatic nucleus (SCN) and endogenous transcriptional-translational feedback loops. Surprisingly, little attention has been given to investigating tauopathy-driven neuropathology in the SCN and the repercussions of SCN and circadian gene dysfunction in the human brain affected by tauopathies. This review aims to provide an overview of the current literature on the vulnerability of the SCN in tauopathies in humans. Emphasis is placed on elucidating the neuronal and glial changes contributing to the widespread disruption of the molecular circadian clock. Furthermore, this review identifies areas of knowledge requiring further investigation.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"4"},"PeriodicalIF":14.9,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10777507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403671","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":"Blood platelet factor 4: the elixir of brain rejuvenation.","authors":"José M Izquierdo","doi":"10.1186/s13024-023-00681-w","DOIUrl":"10.1186/s13024-023-00681-w","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"3"},"PeriodicalIF":14.9,"publicationDate":"2024-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10773073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377990","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":"Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer's disease pathology.","authors":"Joseph Therriault, Marcel S Woo, Gemma Salvadó, Johan Gobom, Thomas K Karikari, Shorena Janelidze, Stijn Servaes, Nesrine Rahmouni, Cécile Tissot, Nicholas J Ashton, Andréa Lessa Benedet, Laia Montoliu-Gaya, Arthur C Macedo, Firoza Z Lussier, Jenna Stevenson, Paolo Vitali, Manuel A Friese, Gassan Massarweh, Jean-Paul Soucy, Tharick A Pascoal, Erik Stomrud, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Serge Gauthier, Henrik Zetterberg, Oskar Hansson, Kaj Blennow, Pedro Rosa-Neto","doi":"10.1186/s13024-023-00689-2","DOIUrl":"10.1186/s13024-023-00689-2","url":null,"abstract":"<p><strong>Background: </strong>Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau₁₈₁, p-tau₂₁₇ and p-tau₂₃₁ with established immunoassay techniques.</p><p><strong>Methods: </strong>We measured p-tau₁₈₁, p-tau₂₁₇ and p-tau₂₃₁ concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau₁₈₁, p-tau₂₁₇ and p-tau₂₃₁. P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity.</p><p><strong>Results: </strong>Mass spectrometry and immunoassays of p-tau₂₁₇ were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau₁₈₁ and p-tau₂₃₁ concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays.</p><p><strong>Conclusions: </strong>Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"2"},"PeriodicalIF":14.9,"publicationDate":"2024-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10773025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377991","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":"Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease","authors":"Lihua Wang, Niko-Petteri Nykänen, Daniel Western, Priyanka Gorijala, Jigyasha Timsina, Fuhai Li, Zhaohua Wang, Muhammad Ali, Chengran Yang, Menghan Liu, William Brock, Marta Marquié, Mercè Boada, Ignacio Alvarez, Miquel Aguilar, Pau Pastor, Agustín Ruiz, Raquel Puerta, Adelina Orellana, Jarod Rutledge, Hamilton Oh, Michael D Greicius, Yann Le Guen, Richard J. Perrin, Tony Wyss-Coray, Angela Jefferson, Timothy J. Hohman, Neill Graff-Radford, Hiroshi Mori, Alison Goate, Johannes Levin, Yun Ju Sung, Carlos Cruchaga","doi":"10.1186/s13024-023-00687-4","DOIUrl":"https://doi.org/10.1186/s13024-023-00687-4","url":null,"abstract":"Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139081910","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":"Microglial APOE4: more is less and less is more","authors":"Ghazaleh Eskandari-Sedighi, Mathew Blurton-Jones","doi":"10.1186/s13024-023-00693-6","DOIUrl":"https://doi.org/10.1186/s13024-023-00693-6","url":null,"abstract":"Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer’s disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138740510","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}