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Mixing Aβ(1-40) and Aβ(1-42) peptides generates unique amyloid fibrils.

Linda Cerofolini, Enrico Ravera, Sara Bologna, Thomas Wiglenda, Annett Böddrich, Bettina Purfürst, Iryna Benilova, Magdalena Korsak, Gianluca Gallo, Domenico Rizzo, Leonardo Gonnelli, Marco Fragai, Bart De Strooper, Erich E Wanker, Claudio Luchinat,

Recent structural studies show distinct morphologies for the fibrils of Aβ(1-42) and Aβ(1-40), which are believed not to co-fibrillize. We describe here a novel, structurally-uniform 1 : 1 mixed fibrillar species, which differs from both pure fibrils. It forms preferentially even when Aβ(1-42) : Aβ(1-40) peptides are mixed in a non-stoichiometric ratio. ... Read more >>

Chem Commun (Camb) (Chemical communications (Cambridge, England))
[2020, 56(62):8830-8833]

Cited: 2 times

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Reactive astrocyte nomenclature, definitions, and future directions.

Carole Escartin, Elena Galea, András Lakatos, James P O'Callaghan, Gabor C Petzold, Alberto Serrano-Pozo, Christian Steinhäuser, Andrea Volterra, Giorgio Carmignoto, Amit Agarwal, Nicola J Allen, Alfonso Araque, Luis Barbeito, Ari Barzilai, Dwight E Bergles, Gilles Bonvento, Arthur M Butt, Wei-Ting Chen, Martine Cohen-Salmon, Colm Cunningham, Benjamin Deneen, Bart De Strooper, Blanca Díaz-Castro, Cinthia Farina, Marc Freeman, Vittorio Gallo, James E Goldman, Steven A Goldman, Magdalena Götz, Antonia Gutiérrez, Philip G Haydon, Dieter H Heiland, Elly M Hol, Matthew G Holt, Masamitsu Iino, Ksenia V Kastanenka, Helmut Kettenmann, Baljit S Khakh, Schuichi Koizumi, C Justin Lee, Shane A Liddelow, Brian A MacVicar, Pierre Magistretti, Albee Messing, Anusha Mishra, Anna V Molofsky, Keith K Murai, Christopher M Norris, Seiji Okada, Stéphane H R Oliet, João F Oliveira, Aude Panatier, Vladimir Parpura, Marcela Pekna, Milos Pekny, Luc Pellerin, Gertrudis Perea, Beatriz G Pérez-Nievas, Frank W Pfrieger, Kira E Poskanzer, Francisco J Quintana, Richard M Ransohoff, Miriam Riquelme-Perez, Stefanie Robel, Christine R Rose, Jeffrey D Rothstein, Nathalie Rouach, David H Rowitch, Alexey Semyanov, Swetlana Sirko, Harald Sontheimer, Raymond A Swanson, Javier Vitorica, Ina-Beate Wanner, Levi B Wood, Jiaqian Wu, Binhai Zheng, Eduardo R Zimmer, Robert Zorec, Michael V Sofroniew, Alexei Verkhratsky,

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear ... Read more >>

Nat Neurosci (Nature neuroscience)
[2021, :]

Cited: 0 times

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The Amyloid Precursor Protein is a conserved Wnt receptor

Tengyuan Liu, Maya Nicolas, Tingting Zhang, Heather Rice, Alessia Soldano, Annelies Claeys, Iveta Petrova, Lee Fradkin, Bart De Strooper, Bassem Hassan,

<h4>SUMMARY</h4> The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the ... Read more >>

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Dementia and COVID-19: a health and research funding crisis.

Liesbeth Aerts, Elsa Lauwers, Bart De Strooper,

Lancet Neurol (The Lancet. Neurology)
[2021, 20(2):90]

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Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores is most accurate when using all genetic information.

Ganna Leonenko, Emily Baker, Josua Stevenson-Hoare, Annerieke Sierksma, Mark Fiers, Julie Williams, Bart De Strooper, Valentina Escott-Price,

There is little agreement regarding the approach and optimal p-value threshold of SNPs to calculate genetic risk scores for Alzheimer’s disease (AD). This reflects a fundamental underlying debate on the polygenic versus oligogenic disease architecture. We re-investigated the assumptions underlying the choice of specific p-value thresholds defining genetic loci used ... Read more >>

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Stem-cell-derived human microglia transplanted into mouse brain to study human disease.

Nicola Fattorelli, Anna Martinez-Muriana, Leen Wolfs, Ivana Geric, Bart De Strooper, Renzo Mancuso,

Microglia are critically involved in complex neurological disorders with a strong genetic component, such as Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Although mouse microglia can recapitulate aspects of human microglia physiology, they do not fully capture the human genetic aspects of disease and do not reproduce all human cell ... Read more >>

Nat Protoc (Nature protocols)
[2021, 16(2):1013-1033]

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Lowering Synaptogyrin-3 expression rescues Tau-induced memory defects and synaptic loss in the presence of microglial activation.

Pablo Largo-Barrientos, Nuno Apóstolo, Eline Creemers, Zsuzsanna Callaerts-Vegh, Jef Swerts, Caitlin Davies, Joseph McInnes, Keimpe Wierda, Bart De Strooper, Tara Spires-Jones, Joris de Wit, Valerie Uytterhoeven, Patrik Verstreken,

Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. Tau binds to Synaptogyrin-3 on synaptic vesicles. Here, we interfered with this function to determine the role ... Read more >>

Neuron (Neuron)
[2021, :]

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The AppNL-G-F mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.

Marjan Vandenabeele, Lien Veys, Sophie Lemmens, Xavier Hadoux, Géraldine Gelders, Luca Masin, Lutgarde Serneels, Jan Theunis, Takashi Saito, Takaomi C Saido, Murali Jayapala, Patrick De Boever, Bart De Strooper, Ingeborg Stalmans, Peter van Wijngaarden, Lieve Moons, Lies De Groef,

In this study, we report the results of a comprehensive phenotyping of the retina of the App<sup>NL-G-F</sup> mouse. We demonstrate that soluble Aβ accumulation is present in the retina of these mice early in life and progresses to Aβ plaque formation by midlife. This rising Aβ burden coincides with local ... Read more >>

Acta Neuropathol Commun (Acta neuropathologica communications)
[2021, 9(1):6]

Cited: 1 time

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Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques

Pranav Preman, Julia TCW, Sara Calafate, An Snellinx, Maria Alfonso-Triguero, Nikky Corthout, Sebastian Munck, Dietmar Rudolf Thal, Alison Goate, Bart De Strooper, Amaia Arranz,

<h4>ABSTRACT</h4> <h4>Background</h4> Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. <h4>Methods</h4> To address ... Read more >>

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Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer's disease.

Lutgarde Serneels, Dries T'Syen, Laura Perez-Benito, Tom Theys, Matthew G Holt, Bart De Strooper,

<h4>Background</h4>Three amino acid differences between rodent and human APP affect medically important features, including β-secretase cleavage of APP and Aβ peptide aggregation (De Strooper et al., EMBO J 14:4932-38, 1995; Ueno et al., Biochemistry 53:7523-30, 2014; Bush, 2003, Trends Neurosci 26:207-14). Most rodent models for Alzheimer's disease (AD) are, therefore, based ... Read more >>

Mol Neurodegener (Molecular neurodegeneration)
[2020, 15(1):60]

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Computational Analysis of Alzheimer Amyloid Plaque Composition in 2D- and Elastically Reconstructed 3D-MALDI MS Images.

Thomas Enzlein, Jonas Cordes, Bogdan Munteanu, Wojciech Michno, Lutgarde Serneels, Bart De Strooper, Jörg Hanrieder, Ivo Wolf, Lucía Chávez-Gutiérrez, Carsten Hopf,

MALDI mass spectrometry imaging (MSI) enables label-free, spatially resolved analysis of a wide range of analytes in tissue sections. Quantitative analysis of MSI datasets is typically performed on single pixels or manually assigned regions of interest (ROIs). However, many sparse, small objects such as Alzheimer's disease (AD) brain deposits of ... Read more >>

Anal Chem (Analytical chemistry)
[2020, 92(21):14484-14493]

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Translating genetic risk of Alzheimer's disease into mechanistic insight and drug targets.

Annerieke Sierksma, Valentina Escott-Price, Bart De Strooper,

To provide better prevention and treatment, we need to understand the environmental and genetic risks of Alzheimer's disease (AD). However, the definition of AD has been confounded with dementia in many studies. Thus, overinterpretation of genetic findings with regard to mechanisms and drug targets may explain, in part, controversies in ... Read more >>

Science (Science (New York, N.Y.))
[2020, 370(6512):61-66]

Cited: 1 time

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Potential human transmission of amyloid β pathology: surveillance and risks.

Elsa Lauwers, Giovanna Lalli, Sebastian Brandner, John Collinge, Veerle Compernolle, Charles Duyckaerts, Gustaf Edgren, Stéphane Haïk, John Hardy, Adel Helmy, Adrian J Ivinson, Zane Jaunmuktane, Mathias Jucker, Richard Knight, Robin Lemmens, I-Chun Lin, Seth Love, Simon Mead, V Hugh Perry, James Pickett, Guy Poppy, Sheena E Radford, Frederic Rousseau, Carol Routledge, Giampietro Schiavo, Joost Schymkowitz, Dennis J Selkoe, Colin Smith, Dietmar R Thal, Tom Theys, Pierre Tiberghien, Peter van den Burg, Philippe Vandekerckhove, Clare Walton, Hans L Zaaijer, Henrik Zetterberg, Bart De Strooper,

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone ... Read more >>

Lancet Neurol (The Lancet. Neurology)
[2020, 19(10):872-878]

Cited: 2 times

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LifeTime and improving European healthcare through cell-based interceptive medicine.

Nikolaus Rajewsky, Geneviève Almouzni, Stanislaw A Gorski, Stein Aerts, Ido Amit, Michela G Bertero, Christoph Bock, Annelien L Bredenoord, Giacomo Cavalli, Susanna Chiocca, Hans Clevers, Bart De Strooper, Angelika Eggert, Jan Ellenberg, Xosé M Fernández, Marek Figlerowicz, Susan M Gasser, Norbert Hubner, Jørgen Kjems, Jürgen A Knoblich, Grietje Krabbe, Peter Lichter, Sten Linnarsson, Jean-Christophe Marine, John C Marioni, Marc A Marti-Renom, Mihai G Netea, Dörthe Nickel, Marcelo Nollmann, Halina R Novak, Helen Parkinson, Stefano Piccolo, Inês Pinheiro, Ana Pombo, Christian Popp, Wolf Reik, Sergio Roman-Roman, Philip Rosenstiel, Joachim L Schultze, Oliver Stegle, Amos Tanay, Giuseppe Testa, Dimitris Thanos, Fabian J Theis, Maria-Elena Torres-Padilla, Alfonso Valencia, Céline Vallot, Alexander van Oudenaarden, Marie Vidal, Thierry Voet, ,

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence ... Read more >>

Nature (Nature)
[2020, 587(7834):377-386]

Cited: 3 times

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Single-Nucleus RNA-Seq Is Not Suitable for Detection of Microglial Activation Genes in Humans.

Nicola Thrupp, Carlo Sala Frigerio, Leen Wolfs, Nathan G Skene, Nicola Fattorelli, Suresh Poovathingal, Yannick Fourne, Paul M Matthews, Tom Theys, Renzo Mancuso, Bart de Strooper, Mark Fiers,

Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-seq is able to detect cellular state in human tissue. Indeed, snRNA-seq analyses of human brain samples have failed to detect a consistent microglial activation ... Read more >>

Cell Rep (Cell reports)
[2020, 32(13):108189]

Cited: 1 time

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Modeling the β-secretase cleavage site and humanizing amyloid-beta precursor protein in rat and mouse to study Alzheimer’s Disease.

Lutgarde Serneels, Dries T'Syen, Laura Perez-Benito, Tom Theys, Matthew Holt, Bart De Strooper,

<h4>Background: </h4> Three amino acid differences between rodent and human APP affect medically important features, including β-secretase cleavage of APP and Aβ peptide aggregation(1–3). Most rodent models for Alzheimer’s disease (AD) are, therefore, based on the human APP sequence, expressed from artificial mini-genes randomly inserted in the rodent genome. While ... Read more >>

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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease.

Wei-Ting Chen, Ashley Lu, Katleen Craessaerts, Benjamin Pavie, Carlo Sala Frigerio, Nikky Corthout, Xiaoyan Qian, Jana Laláková, Malte Kühnemund, Iryna Voytyuk, Leen Wolfs, Renzo Mancuso, Evgenia Salta, Sriram Balusu, An Snellinx, Sebastian Munck, Aleksandra Jurek, Jose Fernandez Navarro, Takaomi C Saido, Inge Huitinga, Joakim Lundeberg, Mark Fiers, Bart De Strooper,

Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer's disease (AD), little is known about the molecular changes and cellular interactions that characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques ... Read more >>

Cell (Cell)
[2020, 182(4):976-991.e19]

Cited: 9 times

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The AppNL-G-F mouse retina is a site for preclinical Alzheimer’s disease diagnosis and research

Marjan Vandenabeele, Lien Veys, Sophie Lemmens, Xavier Hadoux, Géraldine Gelders, Luca Masin, Lutgarde Serneels, Jan Theunis, Takashi Saito, Takaomi Saido, Murali Jayapala, Patrick De Boever, Bart De Strooper, Ingeborg Stalmans, Peter van Wijngaarden, Lieve Moons, Lies De Groef,

In this study, we report the results of a comprehensive phenotyping of the retina of the App NL-G-F mouse. We demonstrate that soluble Aβ accumulation is present in the retina of these mice early in life and progresses to Aβ plaque formation by midlife. This rising Aβ burden coincides with ... Read more >>

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Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer's Disease.

Samuel S Harris, Fred Wolf, Bart De Strooper, Marc Aurel Busche,

Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aβ oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other ... Read more >>

Neuron (Neuron)
[2020, 107(3):417-435]

Cited: 3 times

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Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition.

Emanuela Pasciuto, Oliver T Burton, Carlos P Roca, Vasiliki Lagou, Wenson D Rajan, Tom Theys, Renzo Mancuso, Raul Y Tito, Lubna Kouser, Zsuzsanna Callaerts-Vegh, Alerie G de la Fuente, Teresa Prezzemolo, Loriana G Mascali, Aleksandra Brajic, Carly E Whyte, Lidia Yshii, Anna Martinez-Muriana, Michelle Naughton, Andrew Young, Alena Moudra, Pierre Lemaitre, Suresh Poovathingal, Jeroen Raes, Bart De Strooper, Denise C Fitzgerald, James Dooley, Adrian Liston,

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69<sup>+</sup> CD4 ... Read more >>

Cell (Cell)
[2020, 182(3):625-640.e24]

Cited: 5 times

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Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

Evgenia Salta, Hannah Walgrave, Sriram Balusu, Elke Vanden Eynden, Sarah Snoeck, Katleen Craessaerts, Nicky Thrupp, Leen Wolfs, Katrien Horré, Yannick Fourne, Alicja Ronisz, Edina Silajdžić, Zsuzsanna Callaerts-Vegh, Rudi D’Hooge, Dietmar Rudolf Thal, Henrik Zetterberg, Sandrine Thuret, Mark Fiers, Carlo Sala Frigerio, Bart De Strooper,

<h4>Summary</h4> Adult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel ... Read more >>

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CHCHD2 harboring Parkinson's disease-linked T61I mutation precipitates inside mitochondria and induces precipitation of wild-type CHCHD2.

Tom Cornelissen, Marco Spinazzi, Shaun Martin, Dorien Imberechts, Peter Vangheluwe, Matthew Bird, Bart De Strooper, Wim Vandenberghe,

The T61I mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a protein residing in the mitochondrial intermembrane space (IMS), causes an autosomal dominant form of Parkinson's disease (PD), but the underlying pathogenic mechanisms are not well understood. Here, we compared the subcellular localization and solubility of wild-type (WT) and T61I mutant ... Read more >>

Hum Mol Genet (Human molecular genetics)
[2020, 29(7):1096-1106]

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The β-Secretase BACE1 in Alzheimer's Disease.

Harald Hampel, Robert Vassar, Bart De Strooper, John Hardy, Michael Willem, Neeraj Singh, John Zhou, Riqiang Yan, Eugeen Vanmechelen, Ann De Vos, Robert Nisticò, Massimo Corbo, Bruno Pietro Imbimbo, Johannes Streffer, Iryna Voytyuk, Maarten Timmers, Amir Abbas Tahami Monfared, Michael Irizarry, Bruce Albala, Akihiko Koyama, Naoto Watanabe, Teiji Kimura, Lisa Yarenis, Simone Lista, Lynn Kramer, Andrea Vergallo,

BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-β (Aβ), including Aβ<sub>42</sub>, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity ... Read more >>

Biol Psychiatry (Biological psychiatry)
[2020, :]

Cited: 3 times

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Novel Alzheimer risk genes determine the microglia response to amyloid-β but not to TAU pathology.

Annerieke Sierksma, Ashley Lu, Renzo Mancuso, Nicola Fattorelli, Nicola Thrupp, Evgenia Salta, Jesus Zoco, David Blum, Luc Buée, Bart De Strooper, Mark Fiers,

Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two ... Read more >>

EMBO Mol Med (EMBO molecular medicine)
[2020, 12(3):e10606]

Cited: 7 times

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Axonal Odorant Receptors Mediate Axon Targeting.

Ilaria Zamparo, Simona Francia, Sira Angela Franchi, Nelly Redolfi, Elisa Costanzi, Axelle Kerstens, Yosuke Fukutani, Roberto Battistutta, Patrizia Polverino de Laureto, Sebastian Munck, Bart De Strooper, Hiroaki Matsunami, Claudia Lodovichi,

In mammals, odorant receptors not only detect odors but also define the target in the olfactory bulb, where sensory neurons project to give rise to the sensory map. The odorant receptor is expressed at the cilia, where it binds odorants, and at the axon terminal. The mechanism of activation and ... Read more >>

Cell Rep (Cell reports)
[2019, 29(13):4334-4348.e7]

Cited: 4 times

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