Viral‐induced inflammation is accompanied by β‐amyloid plaque reduction in brains of amyloid precursor protein transgenic Tg2576 mice

Abstract

Amyloid plaques, one of the neuropathological hallmarks of Alzheimer's disease, and their main constituent, the amyloid beta-peptide (Abeta), are triggers of the activation of innate inflammatory mechanisms involving the activation of microglia. To dissect the effects of a non-Abeta-specific microglial activation on the Abeta metabolism, we employed a viral infection-based model. Transgenic mice expressing a mutated form of the human amyloid precursor protein (Tg2576) were used. In preceding experiments, 2-week-old transgenic mice and non-transgenic littermates were infected intracerebrally with the neurotropic Borna disease virus and investigated at 2, 4 and 14 weeks post-infection. The Borna disease virus-inoculated mice showed a persisting, subclinical infection of cortical and limbic brain areas characterized by slight T-cell infiltrates, expression of cytokines and a massive microglial activation in the hippocampus and neocortex. Viral-induced effects reached their peak at 4 weeks post-infection. In 14-month-old Tg2576 mice, characterized by the deposition of diffuse and dense-core amyloid plaques in cortical brain regions, Borna disease virus-induced microglial activation in the vicinity of Abeta deposits was used to investigate the influence of a local inflammatory response on these deposits. At 4 weeks post-infection, histometric analyses employing Abeta immunohistochemistry revealed a decrease of the cortical and hippocampal Abeta-immunopositive area. This overall decrease was accompanied by a decrease of parenchymal thioflavin-S-positive amyloid deposits and an increase of such deposits in the walls of cerebral vessels, which indicates that the elicitation of a non-Abeta-specific microglial activation may contribute to a reduction of Abeta in the brain parenchyma.

Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice

“…Although the factors that initiate inflammation in AD or models of AD are unknown, the present findings suggest that underlying pathology endows a susceptibility to subsequent infection and enhances pathogenic processes; this is broadly consistent with the finding that infection of 3xTg-AD mice with mouse hepatitis virus induced marked tau pathology postinfection (Sy et al, 2011). However Stahl et al (2006) reported that intracerebral infection of Tg2576 mice with the neurotropic Borna disease virus resulted in a decrease in Abcontaining plaques in hippocampus (Stahl et al, 2006). Increases in microglial activation and in expression of inflammatory cytokines were observed, prompting the authors to suggest that an inflammatory environment might enhance clearance of Ab, which has been supported by some groups (Wilcock et al, 2011) but not by others (Koenigsknecht-Talboo and Landreth, 2005;Yamamoto et al, 2007).…”

Recurrent systemic infections with Streptococcus pneumoniae do not aggravate the course of experimental neurodegenerative diseases

“…After intraperitoneal or intracerebral administration of LPS to Tg2576 mice, both an increase in Ab brain concentrations (Sly et al, 2001;Sheng et al, 2003) and a reduction in cerebral Ab levels or cortical plaque burden (DiCarlo et al, 2001;Quinn et al, 2003;Herber et al, 2007) have been observed. Intracerebral infection with borna disease virus led to reduced Ab deposits (Stahl et al, 2006). In our study, concentrations of nonaggregated and aggregated forms of Ab, although tending to be lower in infected animals, were not significantly different, and plaque sizes were almost equal in brains of infected and control mice.…”

Chronic IL-1β-Mediated Neuroinflammation Mitigates Amyloid Pathology in a Mouse Model of Alzheimer’s Disease without Inducing Overt Neurodegeneration

“…Furthermore, a growing body of literature suggests that microglial phagocytosis can play a beneficial role in AD (Wilcock et al, 2004; Barger, 2005; Takata et al, 2007; Chakrabarty et al, 2010). For example, methods used to alleviate amyloid pathology via immune activation include passive or active Aβ immunotherapy (Lemere and Masliah, 2010), acute LPS administration (DiCarlo et al, 2001; Malm et al, 2005), viral infection (Stahl et al, 2006), administration of a nitric-oxide releasing NSAID (Jantzen et al, 2002), and overexpression of the proinflammatory cytokine IL-6 (Chakrabarty et al, 2010). Microglia in neurodegenerative settings have been implicated in mediating the harmful effects of neuroinflammation (Morgan et al, 2005; Town et al, 2005; Wyss-Coray, 2006).…”

“…A growing body of literature has shown that manipulating the neuroinflammatory response toward enhanced microglial activation can lead to phagocytosis of amyloid-β (Aβ) plaques in mouse models of AD (DiCarlo et al, 2001; Jantzen et al, 2002; Malm et al, 2005; Stahl et al, 2006; Lemere and Masliah, 2010). Our laboratory has recently shown that chronic overexpression of IL-1β can produce similar effects (Shaftel et al, 2007a).…”