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Alzheimer's disease and brain aging : modeling, imaging, biomarkers, treatment, evaluation

Maladie d'Alzheimer et vieillissement cérébral : modélisation, imagerie, biomarqueurs, évaluations thérapeutiques

Group leader: Marc Dhenain (CNRS, French Veterinary Academy, National Academy of Medicine)​

Published on 3 July 2018

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  Marc Dhenain (DR2-CNRS)


Understanding and treating brain aging and Alzheimer's disease

Cerebral aging is a public health issue in our societies. It is associated with the appearance of serious pathologies such as Alzheimer's disease. There is currently no cure for these diseases. This lack of treatment is partly related to (i) a poor understanding of the mechanisms associated with these pathologies (ii) the absence of predictive animal models of treatment efficacy (iii) the absence of relevant biomarkers to examine the effectiveness of new treatments in animal models.

Our research group focuses on three central themes to understand cerebral aging and developing therapies against age-related cognitive impairment such as Alzheimer's disease.

1) The characterization animal models to explore physiopathogenic mechanisms associated with age-related brain diseases and to test new therapies.

Our studies are based on transgenic mice that model Alzheimer's disease and on the mouse lemur primate, which is a model of neurodegenerative diseases linked to aging. This animal presents, as it ages, cognitive alterations, alterations of cerebral metabolism, cerebral atrophy and amyloid deposits.

One of our research themes concerns the detection of mechanisms associated with the appearance of cerebral pathologies in these animals and aims to understand these mechanisms by being able to reproduce them. In particular, we are working on the "prion" hypothesis of Alzheimer's disease and have demonstrated that it is possible to induce Alzheimer pathology by inoculation of contaminated tissues.

 
Example of brain atrophy in an aged gray mouse lemur (b) compared with a normal animal (a). 
The image in (c) shows brain glucose use in a gray mouse lemur (PET).


2) The evaluation of new biomarkers of pathological cerebral aging.

We focus in particular on new in vivo microscopic, anatomical and functional biomarkers of pathological cerebral aging. For example, one of our researches focuses on in vivo imaging of amyloid plaques and neurofibrillary degeneration by magnetic resonance imaging (MRI). These lesions are central lesions to the physiopathogenic mechanisms of Alzheimer's disease. More specifically, we have developed Gadolinium staining method which allows the detection of amyloid plaques in vivo. We also developed new markers based on the use of llama antibodies. In addition, we also use markers of cerebral pathologies based on brain metabolism, characterization of neural networks, white matter fibers or markers of neuronal health.

theme-marc-2_large.jpg 
Example of the detection of amyloid plaques (black dots) by nuclear magnetic resonance imaging (resolution 25 x 25 x 90 µm3).


 Example of detection of white matter fibers in the brain of a mouse lemur.


3) The animal models and innovative biomarkers that we develop are used to evaluate new therapies against cerebral aging and Alzheimer's disease.

In particular, we worked on treatments that modulate amyloid load, neurotrophic factors or neuroprotective agents. Some of the treatments we evaluated are tested in clinical phases in humans.


Members of the laboratory associated with these projects

Additional information

See further information here.


Recent publications 

Contrast-enhanced MR microscopy of amyloid plaques in five mouse models of amyloidosis and in human Alzheimer's disease brains.
Dudeffant C.*, Vandesquille M.*, Herbert K., Garin C. M., Alves S., Comoy E., Petit F., Dhenain M. 
Scientific Reports. 2017;7(1):4955.

Chemically-defined gadolinium - single-domain antibody conjugate: a nanoimaging agent for the diagnosis of Alzheimer's disease. 
Vandesquille M.§, Li T.F.§, Po C., Ganneau C., Lenormand P., Dudeffant C., Czech C., Grueninger F., Duyckaerts C., Delatour B., Dhenain M.*, Lafaye P.*, Bay S..
mAbs. 2017;9(6):1016-27.

High Fasting Blood Glucose is an index of early cognitive impairment and hippocampus and-septum atrophy in middle-aged non-human primates. 
Djelti F., Dhenain M., Terrien J.L., Picq J.L., Hardy I., Champeval D., Perret M., Schenker E., Epelbaum J, Aujard F. 
Aging Aging (Albany NY). 2017; 9 (1), 173-186.

In vivo detection of amyloid plaques by gadolinium-stained MRI can be used to demonstrate the efficacy of an anti-Aβ antibody in transgenic mice. 
Santin M.D., Vandenberghe M., Herard A.S., Pradier L., Cohen C., Debeir T., Delzescaux T., Rooney T., Dhenain M..
Frontiers in Aging Neuroscience. 2016, 22 March 2016 

Camelid single-domain antibodies: A versatile tool for in vivo imaging of extracellular and intracellular brain targets. 
Li T.§, Vandesquille M.§, Koukouli F., Dudeffant C., Youssef I., Lenormand P., Ganneau, C., Maskos, U., Czech, C., Grueninger, F., Duyckaerts, C., Dhenain, M., Bay, S., Delatour, B., Lafaye, P. 
Journal of Controlled Release, 2016, 243, pp.1 - 10.