Murray, C. | Search bioRxiv

bioRxiv2018

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

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.

neuroscience↗

bioRxiv2017

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Acute episodes of delirium also contribute significantly to rates of long-term cognitive decline, implying that de novo pathology occurs during these acute episodes. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms has not been investigated. Here we show that systemic inflammation, induced by bacterial LPS, produces both working memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100g/kg) did not affect working memory but robustly impaired contextual fear conditioning (CFC). However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1{beta} replicated, these working memory deficits. Although LPS-induced deficits still occured in IL-1RI-/- mice, systemic TNF- was sufficient to induce similar deficits, indicating redundancy among these cytokines. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits despite failing to block brain IL-1{beta} synthesis. Direct application of IL-1{beta} to ex vivo hippocampal slices induced non-synaptic depolarisation and irrevesible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/- dependent-fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1{beta} but dysfunction leading to neuronal death is mediated by hippocampal IL-1{beta}. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury that may lead to long-term cognitive impairment but that these events are mechanistically dissociable. This would have significant implications for management of cognitive dysfunction and decline during acute illness.

neuroscience↗