Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic Mice

Abstract

Comorbidities that promote the progression of Alzheimer's disease (AD) remain to be uncovered and evaluated in animal models. Because elderly individuals are vulnerable to viral and bacterial infections, these microbial agents may be considered important comorbidities that could potentiate an already existing and tenuous inflammatory condition in the brain, accelerating cognitive decline, particularly if the cellular and molecular mechanisms can be defined. Researchers have recently demonstrated that triggering inflammation in the brain exacerbates tau pathological characteristics in animal models. Herein, we explore whether inflammation induced via viral infection, compared with inflammation induced via bacterial lipopolysaccharide, modulates AD-like pathological features in the 3xTg-AD mouse model and provide evidence to support the hypothesis that infectious agents may act as a comorbidity for AD. Our study shows that infection-induced acute or chronic inflammation significantly exacerbates tau pathological characteristics, with chronic inflammation leading to impairments in spatial memory. Tau phosphorylation was increased via a glycogen synthase kinase-3β-dependent mechanism, and there was a prominent shift of tau from the detergent-soluble to the detergent-insoluble fraction. During chronic inflammation, we found that inhibiting glycogen synthase kinase-3β activity with lithium reduced tau phosphorylation and the accumulation of insoluble tau and reversed memory impairments. Taken together, infectious agents that trigger central nervous system inflammation may serve as a comorbidity for AD, leading to cognitive impairments by a mechanism that involves exacerbation of tau pathological characteristics.

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

“…These changes were associated with increased concentrations of insoluble Ab 1e40 and, albeit to a nonsignificant extent, Ab 1e42 , and increased numbers of Congo redestained Ab-containing plaques in the frontal cortex and hippocampus. 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).…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Lipopolysaccharide (LPS)-induced peripheral inflammation exacerbates tau pathology via CDK5-mediated pathway in a transgenic model of AD (Kitazawa et al 2005). Furthermore, a recent study showed that inflammation induced by infection increased GSK3 activity in the triple-transgenic mouse model of AD; this was associated with a shift of tau from the detergent-soluble to the detergent-insoluble fraction (Sy et al 2011). Another study demonstrated detrimental effects of activated microglia in AD (Qiao et al 2001).…”

Modelling early responses to neurodegenerative mutations in mice

“…Similar studies in mice expressing multiple transgenes at low levels are already generating interesting new data and improving available models (see [44] in this issue of Biochemical Society Transactions). Knockin models should also be combined with environmental stresses to better mimic some of the pathogens, toxins and metabolic stress, etc., to which humans are regularly exposed [45].…”