« homéostasie cérébrale & neuroinflammation » david blum inserm … · 2019. 11. 20. ·...
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« Homéostasie cérébrale & neuroinflammation »
David BLUM
Inserm UMR-S 1172
« Alzheimer & Tauopathies »
DIU MA2
Neuroinflammation and Alzheimer’s Disease
Alzheimer’s disease: lesions
Neurofibrillary,,tangles,
Senile,plaques,
Aloïs Alzheimer 1906
healthy brain
advanced Alzheimer’s
Tsuneya IkezuCagnin et al.
[11C](R)-PK11195 binding
CON
AD
Inflammation is central in Alzheimer’s Disease
Imaging and histology
Karch & Goate, 2015
Unclear impactMicroglia phagocytosis
Macrophage-based inflammation
Innate immunity is central in Alzheimer’s Disease
GWAS
David V. Hansen et al. J Cell Biol doi:10.1083/jcb.201709069
Many GWAS genes are enriched in microglia and interact
David V. Hansen et al. J Cell Biol 2017
Enhanced microglial activation contribute to amyloid pathology
Phagocytosis
Abclearance
Chronic inflammationActivation of microglial inflammasome
Clearance inhibition
Enhanced microglial activation contribute to Tau pathology
PP PP
P
P
P
P
PP
PP P
TauSpreading
PP
PP P
PPP
PP
PP
PP
Neuron
Microglialactivation
Exosomal Tau
P
Detrimentalloop
Cytokines
Tau kinase activationEnhanced Tau
pathology
Reducedfractalkine
Microglial factors directly impair synapses: examples
Hong et al., Science 2016
Complement Cytokines
Polymorphisms in genes associated with antigen
presentation to T cells were identified as susceptibility
loci for Alzheimer’s disease
Adaptive immunity may play a role
T Cell infiltration related to Tau pathology
Zotova et al., Brain 2013
Genetic background = 100% C57Bl6
Schindowski et al., 2006
WT THY-Tau22
3m 7m 12m
AT100
Adj1 Adj2 Opp Target0
10
20
30
40
50
Quadrants
Tim
e s
pen
t (s
)
Adj1 Adj2 Opp Target0
10
20
30
40
50
Quadrants
Tim
e s
pen
t (s
)
***
Adj1 Adj2 Opp Target0
10
20
30
40
50
Quadrants
Tim
e s
pen
t (s
)
*
MWM task
2m 12m WT THY-Tau22
3m 7m 12m
AT100
Adj1 Adj2 Opp Target0
10
20
30
40
50
Quadrants
Tim
e s
pen
t (s
)
Adj1 Adj2 Opp Target0
10
20
30
40
50
Quadrants
Tim
e s
pen
t (s
)
***
Adj1 Adj2 Opp Target0
10
20
30
40
50
Quadrants
Tim
e s
pen
t (s
)
*
MWM task
2m 12m
Memory deficits
Relationship betweenTauopathy and CD8+ T-Cell
brain infiltration
THY-Tau22
FTLDMAPT
T Cell infiltration related to Tau pathology
Laurent et al., Brain 2017
T Cell depletion improves memory in THY-Tau22 mice
Chronic Anti-CD3 injectionsin Tau mice
TCR
T Cell infiltration instrumental to Tau pathology-induced cognitive deficits
Laurent et al., Brain 2017
Targeting immunosuppressive T regulatory cells
Dansokho et al., Brain 2016
Link between neuroinflammationand
brain insulin resistance
Origin of insulin in the brain
Brain insulin is mostly derived from periphery
Saturable transport by EC
Insulin receptor is highly expressed in the hypothalamus
Regulate food intake & peripheral metabolismEnergy expenditure & HPG
Role of insulin in the brain: energy homeostasis
Role of insulin in the brain: learning and memory
Fernandez and Torres-Alemán, 2012Grillo et al., 2015
Insulin receptor is expressed in the brainHighly expressed in hippocampus
Important for memory and plasticity
Ser639Ser612Ser636
Insulin signaling
Alzheimer’s Disease: a « type 3 diabetes »
Alzheimer’s Disease: a « type 3 diabetes »
Impact of AD lesions upon brain insulin signalling
Ab oligomer-induced neuroinflammation leads to insulin resistance
De Felice et al.
Microglialactivation
Involvement of Tau
Marciniak et al., J Exp Med 2017
Involvement of Tau
Amyloïd and Tau lesions (through Tau loss of function)are responsible for brain insulin resistance
...explaining cognitive but also glucose homeostasis impairments of AD patients
Impact of AD lesions upon brain insulin signalling
APP processing IDE
GSK3βO-GlcNacylation
Neuronal insulin resistance
Impact of insulin resistance on lesions
APP processing IDE
GSK3βO-GlcNacylation
Impact of diabetes and peripheral insulin resistance
Neuroinflammation
Neuronal insulin resistance
Perinatalchanges
Peripheral metabolic alterations
Detrimental loop !!
Link between neuroinflammationand
neuromodulation
Main neurotransmitter systems are affected in AD
Glutamate/GABACholinergic system
Monominergic systems (5HT, NA…)Adenosinergic system
Locus coeruleus is early affected in AD
Braak et al., 2011
NA is important for plasticity
Hagena et al., 2016
LC degeneration impacts microglia and AD lesions
Heneka et al., 2010
LC lesions in Tau miceexacerbate inflammation, pTau
and cognitive deficits
Heneka et al., 20
LC lesions exacerbate inflammation, amyloid burden and cognitive deficits in
amyloid models
The case of adenosine
ATP
Adenosine Adenosine
AMP
AMPc
AdenosineKinase
5’-Nucléotidase
PDE
AdenosineDeaminase
Inosine
ATP
5’-Ectonucléotidase (CD73)
ENT
ATPNT
ATP
S-adenosylhomocystéine
SAHhydrolase
Increases in metabolically stressful conditions (nM to mM)
Gi
A1
326aa
A2A
410aa
A2B
332aa
A3
320aa
Gi, Go Gs, Golf Gs, Gq
cAMP(-), PLC(+)Canaux K(+)
PI3K(+)
cAMP(+)PLC(+)
cAMP(+) PLC(+)AA(+)
cAMP(-) PLC(+)PLD(+)
Adenosine receptors
Caffeine is an antagonist of adenosine receptors
Caffeine influences AD risk
Ageing
Life-style(Nutrition, social, exercise…)
Caffeine reduces inflammation & Tau pathologyas well as improves memory in AD models
Temido et al., submitted
Neuronal A2ARs are dysregulated in AD brain
Impact of neuronal A2AR activation in AD models
Neuronal activation of A2ARimpairs plasticity
Neuronal activation of A2ARactivate microglial pathways
Memory defects
Blocking A2ARsimproves
memory in AD models
Conclusion
Neurotransmitters(NA, adenosine,
glutamate….)Insulin
signalling
Innate immunityAdaptive immunity
Homeostasis
Neurotransmitters(NA, adenosine,
glutamate….)Insulin
signalling
Innate immunityAdaptive immunity
Homeostasisdisruption
TauAb
Conclusion
AD lesions disrupt brain homeostasis leading to cognitive deficitsand amplifying lesions
COGNITIVEDEFICITS !