Our science
The challenge of Alzheimer's disease
Alzheimer’s disease affects roughly 10% of the population aged 65 and up to 50% of people aged 85, while the worldwide cost was estimated € 703 billion (World Alzheimer Report 2016). Although the need for novel therapies is great, a deeper understanding of molecular and cellular mechanisms is a prerequisite to make this possible.
Towards a multicellular view
The last years an important paradigm shift has been made. The classical linear cascade from amyloid peptide (Aβ) accumulation, towards Tau pathology, neuronal degeneration and dementia is no longer tenable, and needs to be replaced by a focus on the preclinical phase of Alzheimer's disease which integrates the many novel genes (Sierksma, Science, 2020) into a multicellular view on the disease (De Strooper, Cell 2016).
Gene expression profiling show that microglial and astroglial cells adopt many different states in Alzheimer's, which might explain their disparate roles in the development and progression of the pathology (Chen, Cell, 2020). Single-cell expression profiling opens the door to study those different states at a genome-wide level, providing a unique possibility to determine when, where, in which cell type, and in which disease state, the novel identified Alzheimer's genes are expressed and what cellular pathways are involved.
Our approach
We are generating panels of iPS cells that capture in different ways the genetic risk for Alzheimer's disease and study how this affects morphology, biochemistry, function and transcriptome. From the mapping of their cell state transitions when exposed to accumulating Aβ or Tau pathology, we want to extract the molecular and cellular pathways that contribute to pathogenesis, in a cell specific manner.
In parallel, we use spatial transcriptomics to confirm the changes in human brain samples and benchmark our findings. By identifying critical nodes in the identified gene expression networks, we hope to identify players that can reverse or activate pathways or cell states that are relevant to pathology and could deliver novel drug targets to treat Alzheimer's disease.
Selected publications
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
Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets
Annerieke Sierksma, Valentina Escott-Price, Bart De Strooper
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
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
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
Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission
Heather C Rice, Daniel De Malmazet, An Schreurs, Samuel Frere, Inge Van Molle, Alexander N Volkov, Eline Creemers, Irena Vertkin, Julie Nys, Fanomezana M Ranaivoson, Davide Comoletti, Jeffrey N Savas, Han Remaut, Detlef Balschun, Keimpe D Wierda, Inna Slutsky, Karl Farrow, Bart De Strooper, Joris De Wit