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

Abstract

Acknowledgements. This study was supported by a Wellcome Trust Senior ResearchFellowship to CC (SRF090907) and by NIH R01AG050626. The technical assistance of Gavin MacManus in the Biomedical Sciences Imaging suite is gratefully acknowledged. AbstractAlzheimer's 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 -amyloid pathology to induce exaggerated IL-1 responses to acute stimulation with LPS or IL-1. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1 induction nor NFĸB p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1, NFĸB-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 we demonstrate that astrocytes proximal to A-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, 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.

Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity

“…In the case of the TLR4 response to lipopolysaccharide, microglia exert their effect on astrocytes at least partially through release of soluble mediators that directly activate or facilitate astrocyte responses (Holm and others 2012) and LPS applied directly to purified astrocytes also had very limited effects on astrocyte phenotype in more recent studies (Liddelow and others 2017). These findings are consistent with our own observations: intra-cerebral challenge with LPS triggers the microglia to rapidly synthesise IL-1β, but if this step is by-passed, and the cytokines IL-1γ or TNF-α are directly applied to the hippocampus, the astrocyte population rapidly translocates NFκB to the nucleus and synthesizes chemokines CCL2, CXCL1 and CXCL10 (Hennessy and others 2015; Lopez-Rodriguez and others 2018). Thus, although influence can be exerted in either direction, it is likely that that the microglial cell remains the primary responder to PAMPS and alarmins in most cases and that microglia secrete soluble mediators to drive astrocyte responses.…”

“…Therefore, however the phenotype of astrocytes in these diseases and ageing models might be defined, they clearly can change their phenotype once again upon a subsequent change to their environment: phenotype is plastic and exists on some continuum of different states depending on the local molecular milieu. In the context of chronic neurodegeneration, in which microglia are already primed to produce exaggerated IL-1β responses to subsequent inflammatory stimuli (Cunningham and others 2005; Holtman and others 2015), that astrocytes are also hypersensitive to IL-1 stimulation facilitates an amplification loop (Figure 3) that seems likely to produce a deleterious, NFκB-driven and highly inflammatory astrocyte phenotype (Hennessy and others 2015; Lopez-Rodriguez and others 2018).…”

Delirium

“…IL-1 acts directly on multiple brain cell types 132 . Acute administration of IL-1β and TNF activates astrocytes to produce chemokines (such as CCL2, CXCL1 and CXCL10) and this is also exaggerated in neurodegeneration 85,133 , facilitating the homing of activated leukocytes to the brain. Increased monocyte and neutrophil recruitment contributes to cognitive dysfunction and/or brain damage in mouse models of sepsis, viral encephalitis and postoperative cognitive function [134][135][136] Fig.…”

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium

“…We have modeled delirium, using superimposition of LPS on models of neurodegeneration (Field et al, 2012;Murray et al, 2012;Cunningham and Maclullich, 2013;Lopez-Rodriguez et al, 2018) to produce acute onset, fluctuating deficits in relevant cognitive domains (Davis et al, 2015). These LPS-associated deficits are absent in normal animals but susceptibility to LPS-induced cognitive impairment increases as a function of the underlying neurodegenerative state of the brain (Griffin et al, 2013;Davis et al, 2015).…”