Molecular determinants of Alzheimer’s disease and relative disorders

Team 3 – CNRS UMR9017 – Inserm – Lille University – CHU Lille – Institut Pasteur de Lille

Alzheimer recherche

Presentation

Our project aims to characterize the genetic determinants of neurodegenerative diseases and of Alzheimer’s disease in particular, the leading cause of dementia worldwide, and then to understand their implications in pathophysiological processes. To do this, we are developing high-throughput genomics approaches (genome-wide association studies and / or sequencing) on ​​very large samples of populations of patients and controls thanks to the establishment and coordination of European and global consortia. Once characterized, we develop strategies to assess the physiological and pathological roles of these genetic factors using biochemistry, cell and molecular biology approaches based on cell models (primary cultures / induced pluripotent stem cells) and animals (Drosophila / transgenic mice) as well as high content screenings associated with cell imaging. The combination of these multidisciplinary data allows us to either support the pathophysiological processes already known in Alzheimer’s disease, or to generate new hypotheses allowing a better understanding of the pathology.

Highlights

  • Thanks to European JPND funding, the team set up and coordinates the EADB (European Alzheimer DNA Biobank) consortium, which to date represents the largest global effort in genome-wide analysis (GWAS) to characterize new genetic determinants of Alzheimer’s disease. This study will make it possible to double the number of known genetic determinants of the pathology but also to characterize genetic factors for many variables of interest such as biological markers of cerebrospinal fluid, the risk of cognitive decline or of conversion to dementia.

 

  • The genetic knowledge generated by this work as well as the resulting biological studies also enabled the team to develop a new physiopathological hypothesis for Alzheimer’s disease centered on the synapse and synaptic loss, a very early marker of the development of the pathology. In this hypothesis, a certain number of genetic factors of the disease induce a dysfunction of the synapse and its close environment leading to its disappearance. The team is developing new projects to validate or reject this hypothesis, taking into account the evolution of available genetic data.

Members

Jean-Charles LAMBERT
DR1 Inserm, group leader
Numéro ORCID : 0000-0003-0829-7817

Céline BELLENGUEZ
CRNCN Inserm
Numéro ORCID : 0000-0002-1240-7874

Julien CHAPUIS
MCU, Univ Lille
Numéro ORCID : 0000-0002-5802-2857

Julie DUMONT
MCU, Univ Lille
Numéro ORCID : 0000-0002-6009-0111

Marcos COSTA
CR2, IPL
Numéro ORCID : 0000-0002-4928-2163

Devrim KILINC
CR2, IPL
Numéro ORCID : 0000-0003-3321-5203

Anne-Marie AYRAL
Research engineer, IPL

Benjamin GRENIER-BOLEY
Research engineer, IPL

Florie DEMIAUTTE
Engineer, Univ Lille

Amandine FLAIG
Engineer, IPL

Karine GUYOT
Engineer, IPL

Valérie BUICHE
Technician, IPL

Xavier HERMANT
Technician, IPL

Anaïs Camille VREULX
Technician, IPL

Johanna GADAUT
Technician, IPL

Pierre DOURLEN
Post-doc, Univ Lille

Orthis SAHA
Post-doc, IPL

Dolores SIEDLECKI
Post-doc, Inserm

Alejandra FREIRE
Post-doc, IPL

Bruna MATA SOARES
Post-doc, IPL

Chloé NAJDEK
PhD student

Audrey COULON
PhD student

Erwan LAMBERT
PhD student

Ana Raquel MELO DE FARIAS
PhD student

Julie LEBORGNE
PhD student

Publications

Eysert F, Coulon A, Boscher E, Vreulx AC, Flaig A, Mendes T, Hughes S, Grenier-Boley B, Hanoulle X, Demiautte F, Bauer C, Marttinen M, Takalo M, Amouyel P, Desai S, Pike I, Hiltunen M, Chécler F, Farinelli M, Delay C, Malmanche N, Hébert SS, Dumont J, Kilinc D, Lambert JC, Chapuis J.
Alzheimer’s genetic risk factor FERMT2 (Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner.
Mol Psychiatry. In press.

Sartori M, Mendes T, Desai S, Lasorsa A, Herledan A, Malmanche N, Mäkinen P, Marttinen M, Malki I, Chapuis J, Flaig A, Vreulx AC, Ciancia M, Amouyel P, Leroux F, Déprez B, Cantrelle FX, Maréchal D, Pradier L, Hiltunen M, Landrieu I, Kilinc D, Herault Y, Laporte J, Lambert JC.
BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr348 phosphorylation.
Acta Neuropathol. 2019 Oct;138(4):631-652.

Dourlen P, Kilinc D, Malmanche N, Chapuis J, Lambert JC.
The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis ?
Acta Neuropathol. 2019 Aug;138(2):221-236.

Kunkle BW*, Grenier-Boley B*, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Martin ER, Sleegers K, Badarinarayan N, Jakobsdottir J, Hamilton-Nelson KL, …, Owen MJ, Gudnason V, Mayeux R, Escott-Price V, Psaty BM, Ramirez A, Wang LS, Ruiz A, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P**, Schellenberg GD**, Lambert JC**, Pericak-Vance MA**.
Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
Nat Genet. 2019 Mar;51(3):414-430.

*co-first, **co-last

Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, …, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P.
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease.
Nat Genet. 2013 Dec;45(12):1452-8.


Keywords

Alzheimer ; GWAS ; Sequencing ; Genetics ; Drosophila ; Synapse ; Tau ; Amyloid ; Microglia

Team contact

Jean-Charles Lambert
Research director Inserm (DR1), group leader

jean-charles.lambert@pasteur-lille.fr
03 20 87 73 91