CEA | 31 OCTOBER 2014

Mouse lemur primates

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A biomarker-based approach to follow-up cerebral pathology

CNRS, CEA,

Molecular Imaging Research Center

Fontenay-aux-Roses, France

Marc Dhenain, DVM, PhD

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.

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.

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.

EVALUATION OF FACTORS MODULATING AMYLOID

Exemple of seasonal variations

Dorieux O., non publié

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**

*

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Pla

sm

ati

c A

be

ta (

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 seasonGary et al. in preparation.

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.

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

Err

ors

to

esca

pe

(circu

lar

pla

tfo

rm)

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.

Dhenain et al. Neurobiol Aging. 2000; 21(1):81-8.

ATROPHY IS A PATHOLOGICAL AGING PROCESS

Atrophy evolving rapidly

CS

F v

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(arb

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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.

Dhenain et al. Neurobiol Aging. 2000;21:81-8. ; Kraska et al. Neurobiol Aging.2011; 32: 894–906.

CS

F v

olu

me e

valu

ati

on

(arb

itra

ry u

nit

s)

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.

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 50 550

2

4

6

8

Volume of hippocampus

Fa

sti

ng

blo

od

glu

co

se

(m

mo

l/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.

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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.

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

amyloidosisPrimary 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

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.

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