Hugh Perry - IoW Cafe Scientifique - 11.Apr.11

8/7/2019 Hugh Perry - IoW Cafe Scientifique - 11.Apr.11

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How common infections affect the brain in health anddisease

V. Hugh Perry11th April 2011



Inflammation in the Brain

local brain inflammation

systemic infection and inflammation

Consequence Contributory Cause



Alzheimer¶s Disease

Auguste De

neuronal loss

Amyloid and

neuritic plaques

Neurofibrillary tangles



The death of a nerve cell/neuron

� How does a misfoldedprotein kill the neuron?

� Which part of the neurondies first?

� How does inflammationcontribute to neuronal

death?

4



The death of a nerve cell/neuron

� How does a misfoldedprotein kill the neuron?

� Which part of the neurondies first?

� How does

inflammation

contribute to neuronal

death?

5



Inflammation in Alzheimer¶s disease:

consequence or contributor?

Amyloid plaque

Neurofirbrillary tangle

Nissl & Alzheimer 1910



Macrophages of the brain



Microglia: the first line of defense

Microglia in normal brain

Activated microglia in

response to pathology



� increased numbers of activated microglia

� increased levels of inflammatory molecules (IL-1F, TNF-E, IL-6)

� epidemiology shows protective effects of NSAIDs (e.g. ibuprofen)

Inflammation in Alzheimer¶s disease:

consequence or contributor?

Amyloid plaque

Neurofirbrillary tangle

Nissl & Alzheimer 1910



Model of chronic neurodegeneration: prion disease

Motor impairment:Co-ordination

Strength

0

Clinical

signs

Cognitive impairment:T-maze

DRL

Y-maze

Anhedonia:Burrowing

Glucose intake

Nest building

Asymptomatic

Hyperactive

8 12 16 20wk

Behavioural assays

Pathology assays

� Fatal progressive neurodegenerative disease

� Accumulation of a misfolded amyloid protein�Activation of microglia and increase in number

Nick Rawlins, Rob Deacon



Pathology at 13 weeks

PrP GFAP

Microglia Synaptophysin



Inflammation in chronic neurodegeneration

Despite morphologically activated

microglia:

� No detectable pro-inflammatory

cytokines in brain (unlike AD).

� Robust anti-inflammatory profile:

TGF-ß1 & PGE2.

� Phenotype typically associated with

ingestion/phagocytosis of apoptoticcells.

� Benign inflammatory response.



Pre-synaptic Post-synaptic

Syntaxin mGluR2/3SNAP-25 mGluR1

Rim NMDAR

Synaptophysin PSD-95

CSP AKAP-150

VAMP-2 Homer

Synaptotagmin Shank Rab3 Stargazin

Synapsin

Bassoon

NSF

Munc-18 Other

Hsc70 TubulinComplexin MAP-2

SGT Actin

MitoHSP70

Adhesion

N-Cadherin

B-Catenin

N-Cadherin

B-Catenin

CSP

Rab3

Hsc70

SGT

Synaptophysin

VAMP-2

Synaptotagmin

Synapsin

Rim Syntaxin SNAP-25

Munc-18

Bassoon

NSF

NMDAR mGLUR1

AKAPPSD95

Shank Homer

mGluR2/3

mGluR2/3

MitoHSP70

Actin

MAP-2

Tubulin

Synaptic degeneration

Bryony Gray, Vincent O¶Connor



A B

C D

Zuza Siskova,Anton Page,Vincent O¶Connor



A B

C D



How does inflammation contribute to disease?

16



Sickness Behaviour

Fever Fatigue

Malaise Lethargy

Depression Insomnia

Anorexia Hyperalgesia

Adipsia

««««««««««««««««««««««««««««««««.........

Infection



Sickness Behaviour

Fever Fatigue

Malaise Lethargy

Depression Insomnia


Adipsia

««««««««««««««««««««««««««««««««.........

Infection Localised inflammatory response



-IFN-IFNTNF-etc.

Sickness Behaviour

Fever Fatigue

Malaise Lethargy

Depression Insomnia


Adipsia

««««««««««««««««««««««««««««««««.........

Infection Localised inflammatory response Pro-inflammatory

cytokines



Systemic inflammation activates selective brain regions

21

Harrison et al 2009



The blood brain barrier

Jessica Teeling, Ian Galea, Tracey Newman



Brain disease plus infection

23

+ = ?



Systemic inflammation in prion disease

ACUTE CONSEQUENCES

� Exaggerated sickness behaviour relative to naïve animals

± Increased fever response

± Reduced activity, reduced burrowingCHR ONIC CONSEQUENCES

� Accelerated disease progression

± Increased neuronal loss

± Earlier onset of cognitive decline± Earlier onset of motor impairments

Cunningham et al 2005Cunningham et al 2009



Microglia priming in brain disease: switching function

Colm Cunningham, Jessica Teeling, Katie Lunnon



26Perry et al 2010



A theory has only the possibility of being right

or wrong.

A model has a 3rd possibility -

it may be right but irrelevant!

Manfred Eigen

(Nobel Laureate

1965)



Clinical studies in Alzheimer¶s disease

6 month follow up of 300 AD subjects

± Every 2 months for 6 months

� Memory and Mood assessments

� Carer diary for presence of infections over

the 6 month period

� Blood for a measure of infection and for blood cytokines



Systemic infections in Alzheimer¶s disease

5

1

15

5

3

Urina

ry Tract

infec

tions

Uer

es Trac

t infec

tions

astro

intes

tinal in

fections

hest In

fections

All in

fections

or inf

lammation

Number

f

ubject



Systemic inflammation and cognitive decline

Clive Holmes et al



31

Clive Holmes et al

* * ***

Systemic inflammation and sickness behaviours



Risk factors for Alzheimer¶s Disease

� Diabetes

� Obesity

� Smoking

� Old age



Sickness behaviour

´ not a maladaptive and undesirable effect of illness but rather a highly organised strategy that is at times critical to the survival of the individual if it was living in the wildµ Hart (1988)

´ systemic infection that normally leads to sickness behaviour in an individual with a healthy brain (with no long-term consequences) is distorted and maladaptive in an individual with a diseased brain, leading to inappropriate behaviours and accelerated progression of the brain diseaseµ



Acknowledgements:

Many Colleagues and Collaborators

Funded by:

Alzheimer¶s Society

BBSRC

European Commission

MRC

NC3Rs

Wellcome Trust



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Hugh Perry - IoW Cafe Scientifique - 11.Apr.11

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