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CEA | 31 OCTOBER 2014
Mouse lemur primates
----
A biomarker-based approach to
follow-up cerebral pathology
CNRS, CEA,
Mole...
MOUSE LEMUR PRIMATE
Small size, breeding easy
Survival curve
from 643 mouse lemurs
Languille, S. et al. Ageing Res Rev.
20...
NEUROPATHOLOGY
8 DÉCEMBRE 20168 DÉCEMBRE 2016
Kraska et al, Neurobiol Aging. 2009
Picq et al, Neurobiol Aging. 2012
 Amyl...
NEUROPATHOLOGY
Intracellular amyloid/APP deposits
8 DÉCEMBRE 20168 DÉCEMBRE 2016
Roy et al, Neurobiol Aging.
2015; 36: 149...
EVALUATION OF FACTORS MODULATING AMYLOID
Exemple of seasonal variations
Dorieux O., non publié
**
**
*
***
PlasmaticAbeta(...
Sawiak, S. J. et al, Front Aging Neurosci. 2014
Gradually progressive transformations occurring to evolve
from young brain...
COGNITIVE CONSEQUENCES OF ATROPHY
Behavioral alterations in atrophied aged animals
Picq et al. Neurobiol Aging. 2012; 33(6...
Dhenain et al. Neurobiol Aging. 2000; 21(1):81-8.
ATROPHY IS A PATHOLOGICAL AGING PROCESS
Atrophy evolving rapidly
CSFvolu...
Dhenain et al. Neurobiol Aging. 2000;21:81-8. ; Kraska et al. Neurobiol Aging.2011; 32: 894–906.
CSFvolumeevaluation
(arbi...
Djelti, F. et al. "Impaired Fasting Blood Glucose is associated to cerebral atrophy and cognitive
impairment in middle-age...
C
e
OB
AGING LEADS TO CEREBRAL HYPOMETABOLISM
 Several hypometabolic regions
 Hippocampus, frontal cortex
Glucose metabo...
Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - Feb 2015
Cognitive alterations
Functional
altera...
CONCLUSION
 Aged mouse lemurs display extracellular amyloid and tau lesions
 But with a limited intensity
 Intracellula...
THANK YOU
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Marc Dhenain Alzforum Webinar - Dec 7, 2016

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Presentation made at the Alzforum's live webinar of December 5, 2016, titled "Is Alzheimer’s Disease a Uniquely Human Disorder?" - review additional information and recording at www.alzforum.org/

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Marc Dhenain Alzforum Webinar - Dec 7, 2016

  1. 1. CEA | 31 OCTOBER 2014 Mouse lemur primates ---- A biomarker-based approach to follow-up cerebral pathology CNRS, CEA, Molecular Imaging Research Center Fontenay-aux-Roses, France Marc Dhenain, DVM, PhD
  2. 2. MOUSE LEMUR PRIMATE Small size, breeding easy Survival curve from 643 mouse lemurs Languille, S. et al. Ageing Res Rev. 2012;11(1): 150-162. 1 year 4 years 10 years1 month Short longevity. Possible longitudinal follow-up The mouse lemur is a small primate. You can handle it in your hand and it is easy to breed. It has a short longevity for a primate with a maximal life span of 12 years. We consider it is old at 6 years. Because of this short life span, It is possible to follow-up individual animals during their whole life.
  3. 3. NEUROPATHOLOGY 8 DÉCEMBRE 20168 DÉCEMBRE 2016 Kraska et al, Neurobiol Aging. 2009 Picq et al, Neurobiol Aging. 2012  Amyloidosis (10% of old animals)  Tau lesions (rare)  Amyloid precursor protein (APP) similar to that of humans Bons, …, Selkoe, Neurobiol Aging. 1994 Silhol, Calenda et al., Neurobiol Dis. 1996 The amyloid precursor protein of mouse lemurs is similar to that of humans.This may explain their ability to develop spontaneously amyloid plaques while aging. 10% of the old animals develop these lesions. Tau pathology is more rare, but it is possible to find some lesions in aged animals.
  4. 4. NEUROPATHOLOGY Intracellular amyloid/APP deposits 8 DÉCEMBRE 20168 DÉCEMBRE 2016 Roy et al, Neurobiol Aging. 2015; 36: 149-156. 50µm 10µm In these animals, intracellular amyloid or APP depositions are very obvious.Here, you can see intracellular amyloid labelling in some cells and APP deposits in some other cells.
  5. 5. EVALUATION OF FACTORS MODULATING AMYLOID Exemple of seasonal variations Dorieux O., non publié ** ** * *** PlasmaticAbeta(pg/ml) Mouse lemurs can be used to evaluate parameters modulating amyloid metabolism. For example, we studied the impact of seasons on plasmatic amyloid. In the winter season, middle-aged or old animals present with increased plasmatic amyloid load. The winter season corresponds to a season when lemurs are less active. Winter (Short days) Rest season Summer (Long days) Active season Gary et al. in preparation.
  6. 6. Sawiak, S. J. et al, Front Aging Neurosci. 2014 Gradually progressive transformations occurring to evolve from young brains (Y) to old brains (O1.0) and then to ‘caricatured’ old brains (O1.3 to O5.0). CEREBRAL ATROPHY DURING AGING We evaluated the evolution of the shape of the brains of the animals during aging thanks to MRI exams. Huge changes occur at the level of white matter or at the level of hippocampus. Also, aging leads to increased levels of cerebrospinal fluid (CSF) around the brain.
  7. 7. COGNITIVE CONSEQUENCES OF ATROPHY Behavioral alterations in atrophied aged animals Picq et al. Neurobiol Aging. 2012; 33(6): 1096–1109.  Correlation between atrophy of septal, hippocampal and entorhinal cortex and age-related cognitive alterations Errorstoescape (circularplatform) Young Old Cognitive evaluations in mouse lemurs Relationship between cognitive alterations and cerebral atrophy Cognitive evaluations can be performed in mouse lemurs. Some old animals are good performers while some others are poor performers. There is a relationship between cognitive abilities and cerebral atrophy in old animals.This is true in particular for septal, hippocampal and entorhinal atrophy.
  8. 8. Dhenain et al. Neurobiol Aging. 2000; 21(1):81-8. ATROPHY IS A PATHOLOGICAL AGING PROCESS Atrophy evolving rapidly CSFvolumeevaluation (arbitraryunits) Age (years) 30 - 20 - 10 - 0 - 0 2 4 6 8 10 H H Young Old  Atrophy evolves rapidly in some animals = pathological atrophy Measure of CSF volumes as an index of atrophy How to define pathological atrophy? In a cohort of animals aged from 1 to 10 years, we followed-up CSF volumes in regions surrounding the brain. In some animals atrophy did not evolve strongly whith aging. In some others, atrophy evolved rapidly. We consider that a quick evolution of atrophy reflects a pathological process.
  9. 9. Dhenain et al. Neurobiol Aging. 2000;21:81-8. ; Kraska et al. Neurobiol Aging.2011; 32: 894–906. CSFvolumeevaluation (arbitraryunits) Age (years) 30 - 20 - 10 - 0 - 0 2 4 6 8 10 Animals with amyloid deposits Animals without amyloid deposits ATROPHY IS A PATHOLOGICAL AGING PROCESS Amyloid in atrophied animals  But small extracellular amyloid load: not primary culprit for atrophy The atrophied animals often present with amyloid plaques,….But their amyloid load is often low. This suggests that amyloid deposits are not the primary culprits leading to atrophy. In a more recent study, we suggested that intracellular amyloid/APP load matches with the severity of atrophy.
  10. 10. Djelti, F. et al. "Impaired Fasting Blood Glucose is associated to cerebral atrophy and cognitive impairment in middle-aged non-human primates." Aging. In revision ATROPHY IS A PATHOLOGICAL AGING PROCESS Early glucose dys-homeostasis in atrophied animals  Impairment of fasting blood glucose: a pre-type 2 diabetes condition  Hight glycaemia at the end of the animal resting phase but before food becomes available rs = -0.63 p= 0.0099 30 35 40 45 50 55 0 2 4 6 8 Volume of hippocampus Fastingbloodglucose(mmol/L) It is also possible that cerebral atrophy is not primarily associated to amyloid lesions.We showed impairment of fasting blood glucose in some aged mouse lemurs. This reflects a pre-type 2 diabetes condition. Animals with this pre-type 2 diabetes condition have reduced hippocampal volumes.
  11. 11. C e OB AGING LEADS TO CEREBRAL HYPOMETABOLISM  Several hypometabolic regions  Hippocampus, frontal cortex Glucose metabolism alterations can also be measured by positron emission tomography.This technique revealed age-related changes of glucose uptake in various brain regions such as the hippocampus or the frontal cortex.
  12. 12. Translational Research in Neurological Diseases: Biomarkers, M. Dhenain - Feb 2015 Cognitive alterations Functional alterations Atrophy Mouse lemurs Humans Cognitive alterations Atrophy Biomarkers Tau AmyloidAmyloid Primary alterations (glucose metabolism? other?) BIOMARKER BASED APPROACH Comparisons of data in mouse lemurs and humans Functional alterations Factors modulating amyloidosis Primary alterations ? We propose a biomarker-based approach to compare cerebral pathology in mouse lemurs and in humans. In mouse lemurs early events may be linked to alterations of glucose metabolism or to other biological changes that induce a cascade of events leading to cerebral atrophy. Amyloid may be a consequence of these events and could be modulated by external factors, such as seasonal variations. Tau
  13. 13. CONCLUSION  Aged mouse lemurs display extracellular amyloid and tau lesions  But with a limited intensity  Intracellular amyloid/APP deposits are more easily detected As a conclusion, aged mouse lemurs display extracellular amyloid and tau lesions but with a limited intensity. They also display cerebral atrophy and cerebral metabolic alterations.Lemurs can be used to characterize events leading to these alterations as well as to evaluate therapies.  Aged mouse lemurs display cerebral atrophy, brain metabolic alterations  They can be used to evaluate early events leading to these alterations  Events directly related to the physiopathology of Alzheimer's lesions  Events associated to the physiopathology of aging  Possibility to evaluate the impact of therapeutic interventions  Joseph-Mathurin et al. Neurobiol Aging. 2013; 34: 2613-2622.  Pifferi et al. Journal of Lipid Research. 2015; 56: 1511-1518.
  14. 14. THANK YOU

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