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Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s Disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction

Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s Disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction
Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s Disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction
Introduction: neuroinflammation contributes to Alzheimer’s disease (AD)
progression. Secondary inflammatory insults trigger delirium and may accelerate
cognitive decline. Individual cellular contributors to this vulnerability require elucidation.

Methods: using APP/PS1 mice and AD brain tissue we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons and human brain.

Results: microglia surrounding β-amyloid were primed to produce exaggerated IL-1β upon subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intra-hippocampal IL-1β. Systemic LPS triggered microglial IL-1β, astrocytic chemokines and acute cognitive dysfunction, while IL-1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. IL-1β and IL-6 were elevated in brains of AD patients who died with infection.

Conclusion: the APP/PS1 brain is vulnerable to neuroinflammatory exacerbation at microglial, astrocytic, neuronal and cognitive levels. This phenotypic switch also occurs in human AD. Exacerbation of neuroinflammation, producing sequelae like delirium and accelerated disease progression merits investigation in humans.
1552-5260
Lopez-Rodriguez, Ana Belen
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Hennessy, Edel
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Murray, Carol
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Nazmi, Arshed
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Delaney, Hugh J
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Healy, Daire
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Fagan, Steven
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Rooney, Michael
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Stewart, Erika
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Lewis, Anouchka
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de Barra, Niamh
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Scarry, Philip
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Riggs-Miller, Louise
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Boche, Delphine
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Cunnigham, Mark
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Cunnigham, Colm
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Lopez-Rodriguez, Ana Belen
01c88a04-aa37-410d-83c0-1b1898c9a99f
Hennessy, Edel
813efc13-18fd-4371-8aa1-abdca8cc638e
Murray, Carol
1d16faf6-5f8a-4bae-85bb-0623dae46ea7
Nazmi, Arshed
a97ac208-5799-4b2c-848a-cc1d0c6df441
Delaney, Hugh J
d0996008-8a3d-4b13-9c2b-701e7421cc16
Healy, Daire
ddb5ee88-269b-4dae-bf92-edad0233d316
Fagan, Steven
998a345a-f944-4cd1-b2f4-35045ebf25b0
Rooney, Michael
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Stewart, Erika
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Lewis, Anouchka
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de Barra, Niamh
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Scarry, Philip
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Riggs-Miller, Louise
156c12dc-4ce7-48b5-80be-8442d4c97600
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Cunnigham, Mark
9ccc3ae8-22f2-4843-b339-853eb06a88f7
Cunnigham, Colm
1d42d6d5-91df-4e91-bbb6-5a7559079219

Lopez-Rodriguez, Ana Belen, Hennessy, Edel, Murray, Carol, Nazmi, Arshed, Delaney, Hugh J, Healy, Daire, Fagan, Steven, Rooney, Michael, Stewart, Erika, Lewis, Anouchka, de Barra, Niamh, Scarry, Philip, Riggs-Miller, Louise, Boche, Delphine, Cunnigham, Mark and Cunnigham, Colm (2021) Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s Disease: IL-1β drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimer's & Dementia, [ADJ-D-18-00596R2]. (In Press)

Record type: Article

Abstract

Introduction: neuroinflammation contributes to Alzheimer’s disease (AD)
progression. Secondary inflammatory insults trigger delirium and may accelerate
cognitive decline. Individual cellular contributors to this vulnerability require elucidation.

Methods: using APP/PS1 mice and AD brain tissue we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons and human brain.

Results: microglia surrounding β-amyloid were primed to produce exaggerated IL-1β upon subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intra-hippocampal IL-1β. Systemic LPS triggered microglial IL-1β, astrocytic chemokines and acute cognitive dysfunction, while IL-1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. IL-1β and IL-6 were elevated in brains of AD patients who died with infection.

Conclusion: the APP/PS1 brain is vulnerable to neuroinflammatory exacerbation at microglial, astrocytic, neuronal and cognitive levels. This phenotypic switch also occurs in human AD. Exacerbation of neuroinflammation, producing sequelae like delirium and accelerated disease progression merits investigation in humans.

Text
Submitted ADJ-D-18-00596_R2 - Accepted Manuscript
Restricted to Repository staff only until 2 March 2022.
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More information

Accepted/In Press date: 2 March 2021

Identifiers

Local EPrints ID: 447737
URI: http://eprints.soton.ac.uk/id/eprint/447737
ISSN: 1552-5260
PURE UUID: f1d57c45-b57d-47b8-b670-1ea78acc85af
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

Catalogue record

Date deposited: 19 Mar 2021 17:31
Last modified: 20 Mar 2021 02:37

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Contributors

Author: Ana Belen Lopez-Rodriguez
Author: Edel Hennessy
Author: Carol Murray
Author: Arshed Nazmi
Author: Hugh J Delaney
Author: Daire Healy
Author: Steven Fagan
Author: Michael Rooney
Author: Erika Stewart
Author: Anouchka Lewis
Author: Niamh de Barra
Author: Philip Scarry
Author: Louise Riggs-Miller
Author: Delphine Boche ORCID iD
Author: Mark Cunnigham
Author: Colm Cunnigham

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