« 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

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MWM task

2m 12m WT THY-Tau22

3m 7m 12m

AT100

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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 !