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, 17 (10), [ADJ-D-18-00596R2]. (doi:10.1002/alz.12341).
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.
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