Inflammation in dementia

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Dustin Wells
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1 Inflammation in dementia V. Hugh Perry University of Southampton DPUK April 2018

2 Inflammation in Alzheimer s disease: consequence or contributor? Amyloid plaque Neurofibrillary tangle Nissl & Alzheimer 1910 Karch &Goate (2015)

3 Neuroinflammation Walters et al 2016 Hirsch & Hunot 2009 Walters et al 2016 Jacobs et al 2012 Meraz-Rioz et al 2013

Microglia and macrophages of the CNS Microglia Yolk sac derived and enter CNS in embryo Dynamically interact with their environment Long lived population, locally maintained by mitosis and

4 Microglia and macrophages of the CNS Microglia Yolk sac derived and enter CNS in embryo Dynamically interact with their environment Long lived population, locally maintained by mitosis and apoptosis Diverse functions: Homeostasis Homeostatic transcriptome signature Pathology activated microglia Diverse and plastic transcriptome Perivascular macrophages Immune brain communication

5 Microglia in homeostasis current concepts Clear apoptotic cells Phagocytose molecular debris * Monitor synapse health Trophic support for neurons

6 Microglia and synapse homeostasis Hong, Dissing, Stevens (2016)

7 Synapse pruning in the adult CNS: the pituitary Pow et al 1989

8 Microglia and synaptic plasticity Mittelbron et al (2001) Lawson et al (1990)

18 x 10-6 mm 3 Microglia survey between 174,000-332,000

9 Microglia survey synapses: Which ones? Bartol et al (2015): 449 synapses in (236 presynaptic boutons) in 6x6x5um Krejčova, Diniz et al (2016): volume of microglia territory x 10-6 mm 3 Microglia survey between 174, ,000 synapses in their territory ,0000 synapses Sogn et al (2013): 3.5% synapses with Microglia contact

10 Microglia depletion with icsf1r/c-kit Elmore et al 2015

11 Neuroinflammation and routes to immunomodulation

12 Morphologically activated microglia What activates them - misfolded protein or neurodegeneration? What is their phenotype? Where do they come from recruitment or local proliferation? How do they contribute to disease?

13 Synaptic pruning Stephan AH et al 2012

14 Loss of pre- and post-synaptic elements Is the axon transected by the degeneration of the synapse? Does the spine degenerate or collapse into the dendrite?

15 Loss of pre- and post-synaptic elements Is the axon transected by the degeneration of the synapse? Does the spine degenerate or collapse into the dendrite? No phagocytosis of pre- or post-synaptic components but trogocytosis (Gr, trogo: nibble) of the axon and pre-synaptic elements (Weinhard et al 2018).

16 Synapse disassembly or degeneration Dickins and Salinas 2013

17 Microglia contribute to neuronal and synaptic loss Acute Fitch MT, et al., Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci : Herrera AJ, et al., The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol Dis : Chronic Epstein LG, Gendelman HE. Human immunodeficiency virus type 1 infection of the nervous system: pathogenetic mechanisms. Ann Neurol : Mass E, et al., Somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature :

18 Dynamic microglia phenotype Keren-Shaul et al 2017

19 Strategies to inhibit CSF-1R: immune-modulation by inhibiting microglia proliferation Hume and MacDonald (2012)

20 Inhibition of CSF1R by GW2580 Gomez-Nicola et al (2013)

21 CSF1R inhibition in AD model APP/PS1 Olmos-Alonso et al (2016)

22 CSF1R inhibition in AD model APP/PS1 Olmos-Alonso et al (2016)

23 CSF1R inhibition in AD model 5xfAD with PLX3397 Spangenberg et al 2016

24 Immune to brain communication: a role for microglia Dantzer et al 2012

25 Microglia at the intersection of local and systemic inflammation routes to therapy Homeostasis Phagocytosis Neuroinflammation IL-1 TNF IL-6 N G F GFs NTs Secretome PGE 2 LTs NO ROS Modulate systemic inflammation Modify microglia numbers/phenotype

Neuroinflammation IL-1 TNF IL-6 N G F GFs NTs Secretome PGE 2

26 Microglia at the intersection of local and systemic inflammation routes to therapy Homeostasis Phagocytosis Neuroinflammation IL-1 TNF IL-6 N G F GFs NTs Secretome PGE 2 LTs NO ROS Modulate systemic inflammation Modify microglia numbers/phenotype

Acknowledgements School of Biological Sciences Diego Gomez-Nicola et al Katie Askew, Adrian Olmos-Alonso Jessica Teeling et al Vincent O Connor et al School of Medicine Clive Holmes

27 Acknowledgements School of Biological Sciences Diego Gomez-Nicola et al Katie Askew, Adrian Olmos-Alonso Jessica Teeling et al Vincent O Connor et al School of Medicine Clive Holmes and team CNRS Pisa Matteo Caleo et al Trinity College Dublin Colm Cunningham Funded by: Wellcome Trust MRC ARUK Alzheimer s Society University of Para, Belem Cristovam Diniz et al 27

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

ILSI Europe Satellite Workshop on Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet 03-04 July 2014, Milan, Italy Organised by The ILSI Europe Nutrition and Mental Performance Task Force