Alzheimer's Disease and brain aging: Multimodal imaging and therapy

Leader

Research center

18 route du Panorama
92260 Fontenay-aux-Roses
Philippe Hantraye

Institution

Mircen
CNRS
CEA
Université Paris Sud
Université Paris Saclay
ED568 - Biosigne

Laboratory

Laboratoire des Maladies Neurodégénératives
UMR 9199
Neuratris

Keywords

Alzheimer
imaging
therapy
Nucleation/propagation
Translational research
Available to host a PhD student

Publications

Picq JL#, Villain N, Gary C#, Pifferi F, Dhenain M#, 2015. Jumping stand apparatus reveals rapidly specific age-related cognitive impairments in mouse lemur primates. PLoS ONE. 10, e0146238.

Djelti F, Braudeau J, Hudry E, Dhenain M #, Varin J, Bièche I, Marquer C, Chali F, Ayciriex S, Alves S, Langui D, Potier MC,Duyckaerts C, Miles R, Aubourg P, Cartier N. Excess of brain cholesterol triggers neuronal death and paves the way for Alzheimer’sdisease. Brain.2015.138,2383-2398.

Pifferi F, Dorieux O#, Castellano C A, Croteau E, Masson M, Guillermier M #, Van Camp N, Guesnet P, Alessandri JM, Cunnane S,Dhenain M#, Aujard F. Dietary omega3 polyunsaturated fatty acids enhance resting state brain glucose utilization and reduce anxietyin an adult non-human primate, the grey mouse lemur (Microcebus murinus). J Lipid Res.2015.56(8),1511-1518.

Ben Haim L, Ceyzeriat K, Carrillo de Sauvage MA, Aubry F, Auregan G, Guillermier M, Houitte D, Petit F #, Faivre E, VandesquilleM#, Dhenain M#, Déglon N, Hantraye P, Brouillet E, Bonvento G, Escartin C. The JAK/STAT3 pathway is a common mediator ofastrocyte reactivity in neurodegenerative disease models. J Neuroscience.2015.35(6):2817-2829.

Roy M#, Cardoso C#, Dorieux O#, Malgorn C#, Epelbaum S, Kraska A#, Brouillet E, Delatour B, Perret M, Aujard F, Dhenain M#.Age-associated evolution of plasmatic amyloid in mouse lemur primates: Relationship with neuronal accumulation of amyloid-ßprecursor protein, Neurobiol Aging.2015.36(1):149-156.

Sawiak SJ, Picq JL#, Dhenain M#, Voxel-based morphometry analyses of in-vivo MRI in the aging mouse lemur primate. FrontiersAging Neurosc.2014.6:82.doi:10.3389/fnagi.2014.00082

Fields of research

Neurological and psychiatric diseases

Research Theme

Alzheimer's disease (AD) is a public health problem in our societies. It is associated with the intracerebral accumulation of amyloid plaques and tau lesions. Our team tackles this disease by focusing on three different points. 

1. First we develop imaging procedures to follow-up AD lesions. We develop new MR contrast agents to detect amyloid plaques and tau lesions. Our agents are either non-targeted contrast agents or targeted-contrast agents based on llama antibodies. The agents are tested in mice, macaques and humans. Registration between various imaging modalities required to validate the quality of new contrast agents are based on innovative algorithms developed by our group. In parallel, we develop image processing algorithms to segment amyloid plaques from MRI.

We also develop innovative 3D image processing algorithms to follow-up post mortem markers based on autoradiography (evaluation of cerebral metabolism) or immunohistochemistry (evaluation of amyloid load, tau pathology, neuroinflammation). Our methods allow to perform voxel-wise analyses of 3D-reconstructed post mortem data in order to correlate information coming from various imaging modalities. We are also working on high-resolution virtual microscopy to implement high-throughput analysis of markers such as cell density within entire 3D histological brains. 

Finally, we implement new high performance computing technologies to propose integrated solutions to navigate fluidly and intuitively into big data images (thanks to 3D viewing tablets for example). These solutions allow the comparison of simulation approaches and 3D modelling of preclinical models to identify new therapeutic targets and to develop new drugs against AD on the basis of new digital technologies.

This part of our projects provide a unique opportunity to dive into the brain by integrating multi-scale 3D information from the macroscopic to the microscopic level, and should provide the scientific community with powerful analytical tools to optimize translational research and improve neurodegenerative disease diagnosis, follow up and treatment.

2. A second part of our project concerns the evaluation of new mechanisms involved in Alzheimer's disease. First, we focus on nucleation/propagation hypothesis which suggest that poorly-shaped forms (pathological) of amyloid and tau proteins can transmit their misfolded forms to normal proteins and induce pathology. We seek to understand the reality of these mechanisms in primates and what are the functional consequences of nucleation/propagation processes. We also evaluate the role of mast cells, a critical cell for inflammation, on the development of AD pathology.

3. The last part of our studies concern therapy evaluation in animals and humans. We evaluate immunotherapies against amyloid as a potential treatment against AD. We also evaluate a therapy that target mast cells. The latter therapy is studied in the context of an international phase 3 clinical trial that we drive for images analysis. 

Team members

Thierry Delzescaux
Fanny Petit
Jean-Luc Picq
Anne Sophie Herard
Nicolas Souedet
Nachiket Nadkarni
Cedric Clouchoux
Charlotte Gary
Yael Balbastre
Zhenzhen You
Clement Garin
Clemence Dudeffant
Clement Bouvier
Emmalaurie Baptiste
Lisa Ciaptacz

Lab rotation

Impact of Alzheimer's disease related nucleation propagation mechanisms on functional connectivity

Team leader: 

DHENAIN Marc

Dates: 

January 2, 2018 - June 29, 2018

Application deadline: 

June 29, 2018

Period

~ Jan-March 2018

~ April-June 2018

Project

The project we propose concerns the evaluation of new mechanisms involved in Alzheimer's disease (AD). We focus on nucleation/propagation hypothesis which suggests that poorly-shaped forms (pathological) of amyloid and tau proteins can transmit their misfolded forms to normal proteins and induce pathology. We seek to understand the reality of these mechanisms in rodents and primates and what are the functional consequences of nucleation/propagation processes on neuronal networks (assessed by MRI with resting-state fMRI).

Contact

MIRCen - 18, route du Panorama 92260 Fontenay aux Roses - +33 1 46 54 81 92 - Marc.Dhenain@cea.fr

Supervisor: 

DHENAIN Marc