Microglia activation mediated by toll-like receptor-4 impairs brain white matter tracts in rats.

Yang Xinglong,Xiong Huangui,Zhang Jingdong,Jiang Yanping,Liang Houcheng,Duan Lian

doi:10.7555/jbr.32.20170033

Abstract

Microglia activation and white matter injury coexist after repeated episodes of mild brain trauma and ischemic stroke. Axon degeneration and demyelination can activate microglia; however, it is unclear whether early microglia activation can impair the function of white matter tracts and lead to injury. Rat corpus callosum (CC) slices were treated with lipopolysaccharide (LPS) or LPS + Rhodobacter sphaeroides (RS)-LPS that is a toll-like receptor 4 (TLR-4) antagonist. Functional changes reflected by the change of axon compound action potentials (CAPs) and the accumulation of β-amyloid precursor protein (β-APP) in CC nerve fibers. Microglia activation was monitored by ionized calcium binding adaptor-1 immunofluorescent stain, based on well-established morphological criteria and paralleled proportional area measurement. Input-output (I/O) curves of CAPs in response to increased stimuli were significantly downshifted in a dose-dependent manner in LPS (0.2, 0.5 and 1.0 μg/mL)-treated slices, implying that axons neurophysiological function was undermined. LPS caused significant β-APP accumulation in CC tissues, reflecting the deterioration of fast axon transport. LPS-induced I/O curve downshift and β-APP accumulation were significantly reversed by the pre-treatment or co-incubation with RS-LPS. RS-LPS alone did not change the I/O curve. The degree of malfunction was correlated with microglia activation, as was shown by the measurements of proportional areas. Function of CC nerve fibers was evidently impaired by microglia activation and reversed by a TLP-4 antagonist, suggesting that the TLP-4 pathway lead to microglia activation.

Highlights

Some professionals, like armed policemen, soldiers, alpinists, boxers, and football players, are prone to mild brain trauma and hypoxia associated with environmental extremes, especially when making an urgent move or December 2017 CLC number: R34, Document code: A The authors reported no conflict of interests
We found that the effect of LPS on the function of white matter tract in the corpus callosum (CC) was correlated with microglia activation via the toll-like receptor 4 (TLR-4) pathway rather than through some other nonspecific effects of LPS
The I/O responsive curves of CC fiber compound action potentials (CAPs) were generated by stimulating fiber bundles (Fig. 1)

Summary

Introduction

Like armed policemen, soldiers, alpinists, boxers, and football players, are prone to mild brain trauma and hypoxia associated with environmental extremes, especially when making an urgent move or December 2017 CLC number: R34, Document code: A The authors reported no conflict of interests. According to some in vivo and in vitro studies, reagents that inhibit microglia activation can reverse axon injuries induced by mild brain trauma or hypoxia[14–17]. This raises a question whether activated microglia per se really have an adverse effect on white matter function. Morphological criteria for microglial states are clear: ramified cells indicate a resting state; hyper-ramified to amoeboid cells represent a reactive state; non-ramified hypertrophic microglia represent a phagocytic state[23–25]

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Conclusion