Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

Nature Reviews Neurology, Год журнала: 2020, Номер 17(3), С. 157 - 172

Опубликована: Дек. 14, 2020

Язык: Английский

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PROTAC targeted protein degraders: the past is prologue

Nature Reviews Drug Discovery, Год журнала: 2022, Номер 21(3), С. 181 - 200

Опубликована: Янв. 18, 2022

Язык: Английский

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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

Nature Reviews Neurology, Год журнала: 2019, Номер 15(9), С. 501 - 518

Опубликована: Июль 31, 2019

Язык: Английский

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Tau-targeting therapies for Alzheimer disease

Nature Reviews Neurology, Год журнала: 2018, Номер 14(7), С. 399 - 415

Опубликована: Июнь 12, 2018

Язык: Английский

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Roles of tau protein in health and disease

Acta Neuropathologica, Год журнала: 2017, Номер 133(5), С. 665 - 704

Опубликована: Апрель 6, 2017

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates accompanied by synaptic dysfunction and neural cell death range neurodegenerative disorders, collectively referred to tauopathies. Recent advances our understanding the multiple functions different locations inside outside neurons have revealed novel insights its importance diverse molecular pathways including signalling, plasticity, regulation genomic stability. The present review describes physiological pathophysiological properties how these relate distribution We highlight post-translational modifications tau, which are pivotal defining modulating localisation roles health disease. include discussion other pathologically relevant changes mutation aggregation, aspects impinge on propensity propagate, potentially drive neuronal loss, diseased brain. Finally, we describe cascade events that may be driven dysfunction, impaired axonal transport, alterations synapse mitochondrial function, activation unfolded response defective degradation. It important fully understand attributed since this will provide vital information involvement development pathogenesis Such knowledge enable determination critical should targeted potential therapeutic agents developed for treatment

Язык: Английский

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Neuroinflammation as a Common Feature of Neurodegenerative Disorders

Frontiers in Pharmacology, Год журнала: 2019, Номер 10

Опубликована: Сен. 12, 2019

Neurodegenerative diseases share the fact that they derive from altered proteins undergo an unfolding process followed by formation of -structures, and a pathological tendency to self-aggregate in neuronal cells. This is characteristic tau protein Alzheimer´s disease several tauopathies associated unfolding, synuclein Parkinson huntingtin Huntington disease. Usually self-aggregation products are toxic these cells, toxicity spreads all over different brain areas. We have postulated events molecular alterations trigger neurodegenerative disorders. Most interestingly, occur as result neuroinflammatory cascades involving cross-talks between glial cells neurons consequence activation microglia astrocytes. The model we hypothesized for disease, involve damage signals promote activation, NFβ synthesis release proinflammatory cytokines such TNF-, IL1, IL-6, IL-12 affects receptors with overactivation kinases. These patterns can be applied In this context, involvement innate immunity seems major paradigm pathogenesis diseases. important element search potential therapeutic approaches

Язык: Английский

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Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease

Cell, Год журнала: 2020, Номер 183(6), С. 1699 - 1713.e13

Опубликована: Ноя. 13, 2020

To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map 95 PTMs on multiple isolated from postmortem human tissue 49 AD 42 control subjects. Although PTM maps reveal heterogeneity across subjects, subset display high occupancy frequency for AD, suggesting importance disease. Unsupervised analyses indicate that occur an ordered manner, leading to aggregation. The processive addition minimal set associated with seeding activity was further defined by analysis size-fractionated Tau. summarize, features protein critical intervention at different stages are identified, including enrichment 0N 4R isoforms, underrepresentation C terminus, increase negative charge proline-rich region (PRR), decrease positive microtubule binding domain (MBD).

Язык: Английский

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Tau Kinetics in Neurons and the Human Central Nervous System

Neuron, Год журнала: 2018, Номер 97(6), С. 1284 - 1298.e7

Опубликована: Март 1, 2018

Язык: Английский

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SARS ‐CoV‐2 targets neurons of 3D human brain organoids

The EMBO Journal, Год журнала: 2020, Номер 39(20)

Опубликована: Сен. 2, 2020

Article23 September 2020Open Access Transparent process SARS-CoV-2 targets neurons of 3D human brain organoids Anand Ramani orcid.org/0000-0002-2380-8649 Institute Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Germany Search for more papers by this author Lisa Müller orcid.org/0000-0002-0728-0012 Virology, Medical Faculty, Philipp N Ostermann Elke Gabriel Pranty Abida-Islam Andreas Müller-Schiffmann Neuropathology, Aruljothi Mariappan orcid.org/0000-0001-5286-9806 Olivier Goureau Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France Henning Gruell orcid.org/0000-0002-0725-7138 Faculty Medicine, Cologne, Walker Marcel Andrée Sandra Hauka Torsten Houwaart Microbiology and Hygiene, Hospital, Heinrich-Heine-University Alexander Dilthey Kai Wohlgemuth orcid.org/0000-0003-4092-0664 Department General Pediatrics, Children's Muenster, Heymut Omran orcid.org/0000-0003-0282-6765 Florian Klein German Center Infection Research (DZIF), partner site Bonn-Cologne, Molecular Medicine Cologne (CMMC), Dagmar Wieczorek Ortwin Adams Jörg Timm Carsten Korth Heiner Schaal Corresponding Author [email protected] orcid.org/0000-0002-1636-4365 Jay Gopalakrishnan orcid.org/0000-0002-0639-8705 Information Ramani1,‡, Müller2,‡, Ostermann2,‡, Gabriel1, Abida-Islam1, Müller-Schiffmann3, Mariappan1, Goureau4, Gruell5, Walker2, Andrée2, Hauka2, Houwaart6, Dilthey6, Wohlgemuth7, Omran7, Klein5,8,9, Wieczorek1, Adams2, Timm2, Korth3, *,2 *,1 1Institute 2Institute 3Institute 4Institut 5Institute 6Institute 7Department 8German 9Center ‡These authors contributed equally to work *Corresponding author. Tel: +49 211 811 2393; E-mail: 8111561; The EMBO Journal (2020)39:e106230https://doi.org/10.15252/embj.2020106230 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract COVID-19 pandemic caused infection is public health emergency. typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue rise, suggesting detrimental effects on central nervous system (CNS). Here, we show Düsseldorf isolate enters within 2 days exposure. We identified preferably organoids. Imaging reveal exposure associated with altered distribution Tau from axons soma, hyperphosphorylation, apparent neuronal death. Our studies, therefore, provide initial insights into potential neurotoxic effect emphasize could model CNS pathologies COVID-19. Synopsis Modelling coronavirus critical assess cellular tropism consequences infection. shown enter cerebral target cells. Clinical strain does not appear actively proliferate in neurons. abnormalities induces cell Introduction novel disease 2019 (COVID-19) severe acute syndrome (SARS-CoV-2) spreading worldwide, outbreak continues posing emergency (Worl Health Organization, 2020) . Understanding biology current high priority combatting it efficiently. Thus, essential gain mechanisms SARS-CoV-2, its types tropism, contain short- long-term health. Furthermore, vital establish an experimental allow designing measures how stop viral replication protect rapidly. However, practical problems isolation handling highly infective strains lack reliable vitro systems can efficiently hamper these efforts. patients include upper tract fever, dry cough, dyspnea, indicating first (Yang et al, 2020b). case showed infected suffered sudden complete loss olfactory function, stroke, other (Chen 2020; Helms Poyiadji Sedaghat Karimi, Virani 2020). All infect (CNS) therefore neurotropic (Baig Conde Cardona De Felice Earlier studies SARS-CoV brains mice, since different coronaviruses share similar structure, likely same mechanism possibly invades (McCray 2007). Indeed, report detected presence RNA autopsy samples (Puelles postmortem MRI analysis has hemorrhagic encephalopathy syndromes cause stress inflammations (Coolen at point, utmost test whether directly infects productively replicates CNS. To investigate neurotropism employ suitable recapitulates physiological In regard, recently emerged closely parallel complex neural epithelium exhibiting wide diversity serve as SARS-CoV-2. Induced pluripotent stem cells (iPSCs)-derived have revealed useful development helped variety disorders(Lancaster 2013; 2016; Birey 2017; Gopalakrishnan, Xiang Goranci-Buzhala Notably, others our using unprecedented mechanisms, types, toxicity Zika virus (ZIKV) during recent ZIKV epidemic (Cugola Qian 2017). These validate tool studying only genetic but also environmental hazards brain. readily Neurons invaded cortical area display Tau, Moreover, although organoids, replicate, may support active Results Isolation infectious isolated (SARS-CoV-2 NRW-42) nasopharyngeal oropharyngeal swab specimen patient admitted university hospital, (see Materials Methods section culturing propagation). inoculated African green monkey kidney (Vero CCL-81), performed real-time quantitative polymerase chain reaction (qPCR) culture supernatant. amount drastically increased 0-dpi until 3-dpi (Appendix Fig S1A). Next, analyzed infectivity generated particles propagating virus-containing supernatant yet uninfected Vero confirmed new emergence virus-induced cytopathic (CPEs) increase over 4-dpi. sequence (access number PRJNA627229 European Nucleotide Archive Sample accession NRW-42 which SRS6522060) eight nucleotide exchanges compared Wuhan-Hu-1 isolate. validation convalescent serum detect As April 1, 2020, procure commercial antibodies specifically determine Therefore, tested if they recognize infections experiments. obtained blood four independent individuals who recovered (AB1, AB2, AB3, AB4). Testing them enzyme-linked immunosorbent assay (ELISA) used S1 domain spike protein antigen that, except rest contained SARS-CoV-2-specific IgG S1B). then affinity-purified against full length ORF SARS-CoV-2-N section). Western blots, extracts exposed recognized signal size nucleoprotein recombinant serves positive control experiment S1C). AB4 SARS-CoV-2-infected further specificity AB4, co-immunostaining mouse monoclonal anti-SARS-CoV-2 S polyclonal NP. expected, all S2A). Similarly, somas SARS-CoV-2-positive were labeled antibody S2B). blots SARS-CoV-2-exposed organoid extracts, both bands around 50 180 kDs, sizes uncleaved proteins Together, experiments detects S2C). Before isolate, conditions are well-studied ciliated epithelial (hRECs), (Lamers noticed hRECs (Fig 1A). do this, adapted previously described protocol differentiated two iPSC lines (Donor IMR90 Donor 2, Crx-iPS; brief, started 10,000 iPSCs induced differentiation SB431542 dorsomorphin, TGF beta BMP4 inhibitors, respectively. condition did exogenous addition retinoic acid, activate acid receptors (RAR) induce aberrant (Janesick 2015; 2016, method skips embryoid bodies formation, reduces heterogeneity simultaneously avoiding formation mesoderm endoderm, required ectodermal early stages (Streit 2000). before, exhibit their specific spatially restricted. ventricular zone (VZ) harbors proliferating progenitors (NPCs) elongated nuclei align form lumen, tube-like structure. Cortical positioned basally VZ, forming plate 1B) (Lancaster Knoblich, 2014; Giandomenico Lancaster, 2019). Figure 1. region A. A experiment. (hRECs). Acetylated α-tubulin labels cilia. Arrows point (green). scale bars. Bar diagram right quantifies frequencies hRECs. At least six hREC sections three (n = 3) examined. Data presented mean ± SEM. B. Mock age groups Day-15 (i) and-60 (ii) typical cytoarchitecture L, Zone containing compact palisade-like progenitor (NPCs, blue) CP, TUJ-1-positive (magenta). Note distinct difference TUJ-1 labeling pattern between younger (Day-15) older (Day-60) organoid. Representative images cultured batches derived donor-1 (IMR90) line. C. Compared mock (i), (AB4, green) outer periphery, specified lumen inner where NPCs located, free Magnified (dotted while box) given below. 10 five 5) tested. D. Day-60 Day 15 (magenta) (ii). below, showing perinuclear location E. bar donor (IMR90 Crx-iPS, see Methods). Please note each represents one section. shows enhanced Note, comparative statistics respective post-infection (dpi) significance Asterisks groups. There no significant 2- 4-dpi twelve 4) batches, day post-infections (dpi), analyzed. One-way ANOVA, followed Tukey's multiple comparisons test, ***P < 0.001. F. Subcellular localization High-resolution imaging deconvolution nucleus (gray). 200 White line surrounds border, red encircles nucleus. G. Determination progeny. Supernatants cells, assessed qRT–PCR. While was supernatants supernatants. technical Download figure PowerPoint (Day-15 Day-60) (TCID50/ml equivalent 17.5 PFU/organoid, details) after 4 (dpi). First, began analyzing developmental stage study (Gabriel stage, mostly constitute VZs primitive fewer 1B). pan-neuronal marker VZ 1C Appendix S2D). exclude possibility limited capacity diffusion part intact NPCs' 2D cultures cultures, displayed findings preferred neurons, reported (preprint: Mesci preprint: Song Yang 2020a) S3A). This indeed striking contrast ZIKV, present triggers prematurely differentiate leading congenital microcephaly Analyzing regions significantly higher than suggests prefers relatively mature (Fig. 1D E). signs maturation judged MAP2-positive S100β-positive astrocytes, Iba-1-positive microglial S3B–D). Importantly, virus's 1F). Turning later time (dpi-4 dpi-6) dpi-6 exhibited slightly compromised integrity 1E S4A). Corroborating 1G). vascular, kidney, gut Monteil Zhou angiotensin-converting enzyme (ACE-2), entry receptor expressed types. ACE-2 expression mRNA level via qRT–PCR iPSCs-derived ~12.5- 50-fold lesser (hREC), served S4B). anti-ACE2 ACE2 S4C). Since appears wondered replicate when abundant organotypic slices 60-day-old alternative enhances viability. outgrowths long-range axonal fibers expressing markers MAP2, synapsin-1, PSD95 2019; After exposing localized MAP2 S5A B). slight S5C). demonstrate replicate. co

Язык: Английский

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Update on Alzheimer's Disease Therapy and Prevention Strategies

Annual Review of Medicine, Год журнала: 2017, Номер 68(1), С. 413 - 430

Опубликована: Янв. 14, 2017

Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts understand its basic biology clinical pathophysiology. Significant investments in therapeutic drug discovery programs over past two decades have yielded some important insights but no blockbuster drugs alter course disease. Because significant memory loss cognitive decline are associated with neuron death gray matter, especially frontal cortex hippocampus, focus development has shifted early prevention cellular pathology. Although trial design challenging, due part a lack robust biomarkers predictive value, optimism come from identification study inherited forms early-onset genetic risk factors that provide about molecular pathophysiology potential targets. In addition, better understanding Aβ amyloid pathway tau pathway—leading plaques neurofibrillary tangles, respectively, which histopathological hallmarks AD—continues drive research programs. The main this review summarize most recent biology, biochemistry, pharmacology serve as foundation for more than 50 active advanced-phase trials therapy.

Язык: Английский

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