ILSI Europe Satellite Workshop on Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet July 2014, Milan, Italy

Transcription

1 ILSI Europe Satellite Workshop on Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet July 2014, Milan, Italy Organised by The ILSI Europe Nutrition and Mental Performance Task Force

2 Neuroinflammation - (inflammageing): CNS and systemic inflammation V. Hugh Perry University of Southampton 2

3 Microglia and macrophages of the CNS Microglia Enter CNS in embryo Long lived, dynamically interact with their environment Diverse functions: Homeostasis Pathology activated microglia Perivascular macrophages Immune brain communication 3

4 Regulation of the microglia phenotype CD200 - CD200R CX3CL1 - CX3CR1 XX?- TREM2 CD47- CD172a Sialic acid- Siglec-H 4

5 Multiple activation states of macrophages Macrophage phenotype is plastic and dynamic Sensitised or primed versus Tolerant or adapted Gordon (2003)

6 Inflammation in Alzheimer s disease: consequence or contributor? Nissl & Alzheimer (1910) Marco A. Meraz-Ríos et al (2013) increased numbers of activated microglia, CNS cytokines from ICC, microarray etc (IL-1, TNF, IL-6) epidemiology shows protective effects of NSAIDs (e.g. ibuprofen) GWAS highlights role of innate immunity (CR1, Clu, CD33, Trem2)

7 Activated microglia in prion disease 7

8 Microglia phenotype in prion disease No pro-inflammatory cytokines. Robust anti-inflammatory profile: TGF-ß1 & PGE2 & CCL2. + CSF1, IL-34. Benign inflammatory response.

9 A B C D Siskova et al (2009)

10 Microglia proliferation or recruitment? 10

11 Drivers of microglia proliferation Gomez-Nicola et al (2013)

12 Drivers of microglia proliferation Gomez-Nicola et al (2013)

13 Drivers of microglia proliferation

14 Microglia - contribution to disease progression?

15 Age and co-morbidities Barnett et al (2012)

16 Sickness Behaviour Fever Fatigue Malaise Lethargy Depression Insomnia Anorexia Adipsia Anxiety Hyperalgesia... α-ifn β-ifn TNF-α etc. Infection Localised inflammatory response Pro-inflammatory cytokines

17 Signalling across the blood brain barrier

18 Brain disease plus infection + =?

19 Systemic inflammation in prion disease following bacterial* or viral** mimetics: ACUTE CONSEQUENCES Exaggerated sickness behaviour relative to naïve animals Increased fever response Reduced activity, reduced burrowing Increased cytokine synthesis in brain CHRONIC CONSEQUENCES Accelerated disease progression Increased neuronal loss Earlier onset of cognitive decline Earlier onset of motor impairments Cunningham et al (2005)* Cunningham et al (2009)* Field et al (2010)**

20 Macrophage priming Paniagua et al (2010) (IFN-gamma) MCP-1/CCL2 CCR2 CSF1 and IL-34 CSFR1 Schroder et al (2006)

21 Macrophage diversity Mosser & Edwards (2008)

22 Inhibition of CSF1R by GW2580

23 Inhibition of CSF1R by GW2580

24 Systemic inflammation & CNS disease: microglia activation, proliferation and priming Perry & Holmes (2014)

25 Systemic risk factors for Alzheimer s disease Obesity Smoking Diabetes Periodontitis Old age

26 The interplay between local and systemic inflammation in the CNS The microglia are primed by early stages of ageing, neurodegeneration and systemic inflammation: they retain an innate immune memory of the tissue injury. Systemic inflammation switches an innate response to a more aggressive tissue damaging phenotype contributing to disease symptoms and progression. Systemic immune-to-brain communication, normally part of homeostasis in the healthy brain, becomes maladaptive in the individuals with a diseased or injured CNS. Monitoring and prompt treatment of systemic disease, inflammation and infection may delay disease progression and improve quality of life.

27 Acknowledgements CNSIG Katie Lunnon Bryony Gray Deji Asuni Zuza Siskova Hussain Al-Malki Katya Malfi Ursula Püntener Steve Booth Diego Gomez-Nicola School of Biological Sciences Jessica Teeling Vincent O Connor University of Oxford Nick Rawlins Rob Deacon University of Ulster Christian Holscher Funded by: Wellcome Trust MRC ARUK Alzheimer s Society School of Medicine Clive Holmes and colleagues Anton Page 27

28 Thank you