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bioRxiv · 10.1101/344218

Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

Lopez-Rodriguez, A. B.·Hennessy, E.·Murray, C.·Lewis, A.·de Barra, N.·Fagan, S.·Rooney, M.·Nazmi, A.·Cunningham, C.
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Abstract

Alzheimers disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by {beta}-amyloid pathology to induce exaggerated IL-1{beta} responses to acute stimulation with LPS or IL-1{beta}. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1{beta} induction nor NF{kappa}B p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1{beta}, NF{kappa}B-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1{beta} we demonstrate that astrocytes proximal to A{beta}-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1{beta}, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

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Lopez-Rodriguez, A. B., Hennessy, E., Murray, C., Lewis, A., de Barra, N., Fagan, S., Rooney, M., Nazmi, A., Cunningham, C.. 2018-06-11. Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits. https://doi.org/10.1101/344218

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