Olene Dorieux

The grey mouse lemur: a non-human primate model for ageing studies.

The use of non-human primate models is required to understand the ageing process and evaluate new therapies against age-associated pathologies. The present article summarizes all the contributions of the grey mouse lemur Microcebus murinus, a small nocturnal prosimian primate, to the understanding of the mechanisms of ageing. Results from studies of both healthy and pathological ageing research on the grey mouse lemur demonstrated that this animal is a unique model to study age-dependent changes in endocrine systems, biological rhythms, thermoregulation, sensorial, cerebral and cognitive functions.

Age-associated cerebral atrophy in mouse lemur primates

We assessed the regional brain atrophy in mouse lemur primates from 4.7T T2-weighted magnetic resonance images. Thirty animals aged from 1.9 to 11.3 years were imaged. Sixty-one percent of the 23 animals older than 3 years involved in the study displayed an atrophy process. Cross-sectional analysis suggests that the atrophy follows a gradual pathway, starting in the frontal region then involving the temporal and/or the parietal part of the brain and finally the occipital region. Histological evaluation of five animals selected according to various stages of atrophy suggested that extracellular amyloid deposits and tau pathology cannot explain by themselves this atrophy and that intracellular amyloid deposition is more closely linked to this pathology. This study suggests that most of the age-related atrophy occurring in mouse lemurs is caused by one clinical, evolving, pathological process. The ability to follow this pathology non-invasively by MRI will allow to further characterize it and evaluate its relationship with neuropathological lesions that are involved in human diseases such as Alzheimer.

In Vivo Cross-sectional Characterization of Cerebral Alterations Induced by Intracerebroventricular Administration of Streptozotocin

Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimers disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.

Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur

Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months’ supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze.jlr Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety.

Age-associated evolution of plasmatic amyloid in mouse lemur primates: relationship with intracellular amyloid deposition

Alzheimers disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-β peptide (Aβ) deposition in the brain is one of its hallmarks, and the measure of plasma Aβ is considered to be a biomarker for anti-amyloid drug efficacy in animal models of AD. However, age-associated plasmatic Aβ modulation in animal models is practically never addressed in the literature. Mouse lemur primates are used as a model of normal and AD-like cerebral aging. Here, we studied the effect of age on plasmatic Aβ in 58 mouse lemurs aged from 1 to 10 years. A subset of animals presented high plasmatic Aβ, and the proportion of animals with high plasmatic Aβ was higher in aged animals as compared with young ones. Histologic evaluation of the brain of some of these animals was carried out to assess extracellular and intracellular amyloid load. In aged lemurs, plasmatic Aβ was negatively correlated with the density of neurons accumulating deposits of Aβ.

Characterization of blood biochemical markers during aging in the Grey Mouse Lemur (Microcebus murinus): impact of gender and season

BackgroundHematologic and biochemical data are needed to characterize the health status of animal populations over time to determine the habitat quality and captivity conditions. Blood components and the chemical entities that they transport change predominantly with sex and age. The aim of this study was to utilize blood chemistry monitoring to establish the reference levels in a small prosimian primate, the Grey Mouse Lemur (Microcebus murinus).MethodIn the captive colony, mouse lemurs may live 10–12 years, and three age groups for both males and females were studied: young (1–3 years), middle-aged (4–5 years) and old (6–10 years). Blood biochemical markers were measured using the VetScan Comprehensive Diagnostic Profile. Because many life history traits of this primate are highly dependent on the photoperiod (body mass and reproduction), the effect of season was also assessed.ResultsThe main effect of age was observed in blood markers of renal functions such as creatinine, which was higher among females. Additionally, blood urea nitrogen significantly increased with age and is potentially linked to chronic renal insufficiency, which has been described in captive mouse lemurs. The results demonstrated significant effects related to season, especially in blood protein levels and glucose rates; these effects were observed regardless of gender or age and were likely due to seasonal variations in food intake, which is very marked in this species.ConclusionThese results were highly similar with those obtained in other primate species and can serve as references for future research of the Grey Mouse Lemur.

Longitudinal in vivo micro-anatomic follow-up of amyloid plaque load by MRI

polycarbonate. The average signal intensity of tissue surrounding the lateral ventricles was measured in 3T T1-weighted MRI images from ten subjects with AD in the ADNI database. The mixture found to replicate this tissue was made of 2% (w/v) agar dissolved in water, containing 0.01% (w/v) NaCl and a gadopentetate dimeglumine concentration of 0.0375 mM. A brain-shaped mold was filled with tissue-mimicking solution and the ventricle positioned in the middle of the brain. The completed phantom was scanned using the ADNI-specific MP-RAGE sequence. Images were analyzed using a fully-automated segmentation tool. Results: The signal intensity difference between the ventricle and agar solution successfully matched in-vivo signal intensity differences. At a resolution of 1.0 x1.0 x1.0 mm, a volume of 46.6 cm was reported, which is only 2.3% smaller than the actual volume. This result illustrates that the software used does a reasonable job of estimating ventricle volume. The use of the ventricle phantom allowed us to also pinpoint ventricular sub-regions where the algorithm failed. Conclusions: A life-sized MRI-compatible brain ventricle phantom was successfully created. Images acquired are available from the authors to groups wishing to use this data for validation. As enlargement of the ventricles is further established as a marker of disease progression and incorporated into clinical trials, careful validation using gold standards must be performed to ensure the integrity of the study.

Invivo detection of age-related cerebral glucose uptake alterations by PET in microcebus murinus primates

e Laval and Centre de Recherche Universit e Laval Robert Giffard, Quebec, Quebec, Canada; David Geffen School of Medicine at UCLA, Los Angeles, California, United States; 4 University of Alberta, Edmonton, Alberta, Canada; 5 Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; New York University School of Medicine, Center for Brain Health, New York, New York, United States; 7 Rush University, Chicago, Illinois, United States; Boston University School of Medicine, Boston, Massachusetts, United States; Center for NeuroImaging Research CENIR and Universit e Pierre et Marie Curie, Paris, France; 10 University of Frankfurt/Main, Frankfurt, Germany; 11 McGill University, Montreal, Quebec, Canada; University of Eastern Finland, Kuopio, Finland; Wayne State University School of Medicine, 8D-University Health Center, Detroit, Michigan, United States; 14 Mayo Clinic and Foundation, Rochester, Minnesota, United States.

MRI evaluation of focal brain lesions in streptozotocin-treated animals: Comparison between rodents (rats) and primates (microcebus murinus)

STREPTOZOTOCIN-TREATED ANIMALS: COMPARISON BETWEEN RODENTS (RATS) AND PRIMATES (MICROCEBUS MURINUS) Audrey Kraska, Mathieu Santin, Marc Dhenain, Hantraye Philippe, Olene Dorieux, Marion Chaigneau, Martine Guillermier, Diane Houitte, Charl ene Josephine, Martine Perret, Nelly Joseph-Mathurin, Fabienne Aujard, Pierre Lestage, URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses, Pantin, France; 2 Sanofi-Aventis, Chilly-Mazarin; 3 CNRS, Fontenay-aux-Roses; 4 URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses; CNRS, Brunoy; URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses; URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses; 8 UMR 7179 CNRS-MNHN, Brunoy; 9 URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses; UMR 7179 CNRS-MNHN, Brunoy; Institut de recherches Servier, Croissy-sur-Seine.

Links between cerebral atrophy, behavioral alterations and neuropathological changes in mouse lemur primates

BEHAVIORAL ALTERATIONS AND NEUROPATHOLOGICAL CHANGES IN MOUSE LEMUR PRIMATES Marc Dhenain, Audrey Kraska, Nadine Mestre-Frances, Olene Dorieux, Fanny Petit, Emmanuel Bourrin, Anne-Sophie Herard, Evelyne Chenu, Andreas Volk, Martine Perret, Philippe Hantraye, Fabienne Aujard, Jean-Luc Picq, URA CEA CNRS 2210, Fontenay aux Roses, France; URA CEA CNRS 2210, Orsay, France; INSERM U710EPHE, Montpellier, France; Institut Curie, Orsay, France; CNRS UMR 7179, MNHN, Brunoy, France; E.A. 2027, Université Paris 8, St Denis, France. Contact e-mail: Marc.Dhenain@cea.fr