Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by Toxocara canisin mice

Abstract

BackgroundBecause the outcomes and sequelae after different types of brain injury (BI) are variable and difficult to predict, investigations on whether enhanced expressions of BI-associated biomarkers (BIABs), including transforming growth factor β1 (TGF-β1), S100B, glial fibrillary acidic protein (GFAP), neurofilament light chain (NF-L), tissue transglutaminases (tTGs), β-amyloid precursor proteins (AβPP), and tau are present as well as whether impairment of the ubiquitin-proteasome system (UPS) is present have been widely used to help delineate pathophysiological mechanisms in various BIs. Larvae of Toxocara canis can invade the brain and cause BI in humans and mice, leading to cerebral toxocariasis (CT). Because the parasitic burden is light in CT, it may be too cryptic to be detected in humans, making it difficult to clearly understand the pathogenesis of subtle BI in CT. Since the pathogenesis of murine toxocariasis is very similar to that in humans, it appears appropriate to use a murine model to investigate the pathogenesis of CT.MethodsBIAB expressions and UPS function in the brains of mice inoculated with a single dose of 250 T. canis embryonated eggs was investigated from 3 days (dpi) to 8 weeks post-infection (wpi) by Western blotting and RT-PCR.ResultsResults revealed that at 4 and 8 wpi, T. canis larvae were found to have invaded areas around the choroid plexus but without eliciting leukocyte infiltration in brains of infected mice; nevertheless, astrogliosis, an indicator of BI, with 78.9~142.0-fold increases in GFAP expression was present. Meanwhile, markedly increased levels of other BIAB proteins including TGF-β1, S100B, NF-L, tTG, AβPP, and tau, with increases ranging 2.0~12.0-fold were found, although their corresponding mRNA expressions were not found to be present at 8 wpi. Concomitantly, UPS impairment was evidenced by the overexpression of conjugated ubiquitin and ubiquitin in the brain.ConclusionFurther studies are needed to determine whether there is an increased risk of CT progression into neurodegenerative disease because neurodegeneration-associated AβPP and phosphorylated tau emerged in the brain.

The significance of cerebral toxocariasis: a model system for exploring the link between brain involvement, behaviour and the immune response

“…Astrocyte activation as evidenced by enhanced expression of GFAP was also observed in infected animals. This parallels the observations of Liao and colleagues (Liao et al, 2008a).…”

“…Liao and colleagues stated that the effects of Toxocara in the brain in humans are likely to be too cryptic to be clinically detected because the parasite burden is light and thus the neuropathogenesis and sequelae of subtle brain injury in cerebral toxocariasis remain unclear (Liao et al, 2008a). In their view, the murine model could be used to detect these subtle effects.…”

“…Liao and colleagues (Liao et al, 2008b) also investigated blood-brain barrier impairment in experimental cerebral toxocariasis, as measured by cerebral Evans blue (EB) concentration, pathological changes and glial fibrillary acidic protein (GFAP). Blood-brain barrier permeability (EB) and injury (GFAP) increased with infection duration but these effects did not appear to relate to larval numbers (although these were low, as described above).…”

Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

“…Experimental work in mice has established evidence that may have implications for human health, such as the following: larvae recovered from the murine brain differ in number between genetically different inbred mice inoculated with the same dose (189), the distribution of larvae may not be random in the brain (190,191), behavioral alterations are dose dependent (198), cerebral infection can lead to deficits in memory and learning (189), and infection in the brain induces an inflammatory immune response (82,200). Given the central role of cytokines in the brain under normal or disease conditions, prolonged exposure to proinflammatory cytokines that promote neural injuries, e.g., tumor necrosis factor alpha (TNF-␣), IL-6, and IL-1␤, may aggravate neurodegenerative progression and compromise vulnerable neurons (201).…”

“…A role for Foxp3 ϩ CD4 ϩ CD25 ϩ T regulatory (Treg) cells in the regulation of immunopathology, including granuloma development in murine models of toxocaral hepatitis, and in the enhanced expression of transforming growth factor ␤1 (TGF-␤1) was recently suggested. TGF-␤1 is important for the function and local survival of Treg cells during larval migration in the muscle, small intestine, brain, and liver of the mouse (80)(81)(82). The potential susceptibility loci of HLA class II molecules are considered to be involved in regulating Th2-dominant immunity (controlled by Foxp3 ϩ CD4 ϩ CD25 ϩ Treg cells by stimulation through TGF-␤1), creating an environment that benefits larvae but potentially contributes to organ damage (81).…”