AGAD - AGing And Dementia

Principal Investigator

Pascal Kienlen-Campard, PhD

Postdoctoral Researcher

Nuria Suelves Caballol, PhD, (FNRS Postdoctoral Researcher)

Jithu Anrudhan, PhD

PhD students

Louise Deltenre, MSc, (PhD student, FRS-FRIA Research fellow)
Marion Dourte, MSc, (PhD student)
Shirine Saleki, MSc (PhD student, FNRS Research fellow)
Debora Palomares Pedroviejo, MSc (PhD student, FRS-FRIA Research fellow)
Axelle Vanparys, MSc, (PhD student, FNRS Research fellow)

Laboratory Technicians

Esther Paître
Marine Van Calsteren

Ioanna and Axel Sandvig, Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

Steven O. Smith, Center for Structural Biology, Stony Brook University, New York, USA

Serena Stanga, Neuroscience Institute Cavalieri Ottolenghi, University of Torino, Italy

Federico Forneris, Armenise-Harvard Laboratory, Department of Biology and Biotechnology, University of Pavia, Italy

Sébastien Hébert, Department of Psychiatry and Neurosciences, Université Laval, Québec, Canada

Loïc Quinton, Molecular Systems (MolSys), ULiège, Belgium

Dietmar R. Thal, Laboratory for Neuropathology, KULeuven, Belgium

Patricia Renard, Namur Research Institute for Life Sciences (Narilis), UNamur, Belgium

Boulouki Ayeh, UNamur

Exploring the relationship between brain senescence and the progression of AD lesions. Though aging has long been recognized as the major risk factor for Alzheimer’s disease (AD), our understanding of cellular and molecular processes underlying the biological aging of the brain and their link with the onset of AD pathology remain too elusive. The accumulation of resident senescent cells is thought to be a driver of pathological aging of the brain in neurodegenerative diseases. In this project, we aim first at characterizing the molecular and cellular signatures of pathological aging, with a particular focus on mitochondrial dysfunction and autophagy-related process. This is carried out in mouse models presenting accelerated senescence. By crossing these senescent models with the latest generation of APP knock-in mice (amyloid pathology) or tau transgenic mice, we investigate the mechanisms linking pathological aging to AD lesions. A collaboration with I. and A. Sandvig at NTNU (Trondheim) is established to generate in vitro neural networks through reverse engineering to evaluate the consequence of these processes on neuronal activity and function.

Identifying and validating blood biomarkers for early asymptomatic detection of AD and tauopathies. Blood biomarkers hold significant promise for the diagnosis and monitoring of neuropathologies due to their accessibility through a simple blood test. We are developing rigorous, standardised protocols for measuring plasma biomarkers using highly sensitivity techniques (Single Molecular Array, SIMOA). Our biobank currently contains around 500 plasma samples from cognitively normal individuals or individuals at different stages of AD. Our particular focus is on parameters that allow the identification of preclinical cases at high risk of developing the symptoms of the disease.

Unravelling the link between Presenilin-dependent changes in lipid homeostasis and Aβ production. The identification of the ApoE4 allele as the major risk factor in AD has directed a great deal of attention towards cholesterol metabolism and transport in the context of the disease. Presenilins are primarily known as the catalytic subunits the γ-secretase that produce β-amyloid peptides, the main components of the senile plaques. Transcriptome analyses have drawn our attention to the role of Presenilins (PSs) in the expression of genes associated with lipid metabolism. We explore here the hypothesis that an alteration of Presenilins function (loss-of-function, mutations) could disrupt lipid homeostasis and subsequently trigger amyloid pathology, eventually impairing brain function. This project involves spatial lipidomic analysis carried out with the team of L. Quinton, ULiège.

Progression of tauopathies in olfactory regions. A growing body of evidence indicates that loss of olfactory function is predictive of subsequent neurodegenerative pathologies. Our project, led by a consortium of clinicians and fundamental researchers (including C. Huart, B. Hanseeuw, A. Decottignies, UCLouvain; P. Renard, UNamur), is developing an innovative approach using nasal brushing to study the appearance of pathological biomarkers (senescence, amyloid and tau pathology) in the olfactory epithelium. The early appearance of these biomarkers could be a source of pathological material that then spreads to the CNS via the olfactory pathways. We are studying these hypotheses in mouse models of tauopathy and comparing the results with human tissue.

Specific conformations and posttranslational modifications (PTMs) involved in the formation of pathological protein aggregates found in AD. We have developed over time a cutting-edge expertise in studying transmembrane protein interactions and particularly APP homo-interaction in the context of AD. A first goal of our project is to analyse how mechanisms driving APP dimerization and controlling specific dimeric conformations lead to the formation of pathogenic Aβ assemblies. An assumption here is that conformations and membrane orientations driven by motifs present in the Aβ sequence could be either protective or aggravating for the formation of Aβ oligomers (in collaboration with S. Constantinescu, UCLouvain). More recently (in collaboration with B. Hanseeuw and D. Vertommen, UCLouvain), we contributed to the finding that ubiquitination at specific positions of the soluble tau protein distinguishes AD from primary tauopathies. Distinct PTMs and protein-protein interactions appear thus as a driving force shifting AD proteins from physiological to pathological conformations. This leads us here, by combining mass spectrometry and viral transduction approaches, to investigate how different ubiquitination profiles contribute to the progressive onset of neurofibrillary tangles.

Boyer, Emilien, Deltenre, Louise, Dourte, Marion, Colmant, Lise, Paître, Esther, Sleegers, Kristel, Suelves Caballol, Nuria, Hanseeuw, Bernard & Kienlen-Campard, Pascal (2024). Comparison of plasma soluble and extracellular vesicles-associated biomarkers in Alzheimer's disease patients and cognitively normal individuals. Alzheimer's research & therapy, 6(1), 141 [1-14[. doi :10.1186/s13195-024-01508-6. http://hdl.handle.net/2078.1/288958

Suelves, Nuria, Saleki, Shirine, Ibrahim, Tasha, Palomares, Debora, Moonen, Sebastiaan, Koper, Marta J, Vrancx, Céline, Vadukul, Devkee M, Papadopoulos, Nicolas, Viceconte, Nikenza, Claude, Eloïse, Vandenberghe, Rik, von Arnim, Christine A F, Constantinescu, Stefan N., Thal, Dietmar Rudolf, Decottignies, Anabelle & Kienlen-Campard, Pascal (2023). Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology. Acta neuropathologica communications, 11, 82. doi :10.1186/s40478-023-01578-x. http://hdl.handle.net/2078.1/275259

Kyalu Ngoie Zola, Nathalie, Balty, Clémence, Pyr dit Ruys, Sébastien , Vanparys, Axelle A. T. , Huyghe, Nicolas D. G. , Herinckx, Gaëtan, Johanns, Manuel, Boyer, Emilien, Kienlen-Campard, Pascal, Rider, Mark H. , Vertommen, Didier & Hanseeuw, Bernard (2023). Specific post-translational modifications of soluble tau protein distinguishes Alzheimer’s disease and primary tauopathies. Nature Communications, 14, doi :10.1038/s41467-023-39328-1.
http://hdl.handle.net/2078.1/275792

Vrancx, Céline, Vadukul, Devkee M, Suelves Caballol, Nuria, Contino, Sabrina, D'Auria, Ludovic, Perrin, Florian, van Pesch, Vincent, Hanseeuw, Bernard, Quinton, Loïc & Kienlen-Campard, Pascal (2021). Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies. Molecular neurobiology, doi :10.1007/s12035-021-02567-8.
http://hdl.handle.net/2078.1/253777

Perrin, Florian, Papadopoulos, Nicolas, Suelves, Nuria, Opsomer, Rémi, Vadukul, Devkee M, Vrancx, Céline, Smith, Steven O, Vertommen, Didier, Kienlen-Campard, Pascal & Constantinescu, Stefan N. (2020). Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization. iScience, 23, 101887. doi :10.1016/j.isci.2020.101887
http://hdl.handle.net/2078.1/264778