Brain injury induces cholesterol 24-hydroxylase (Cyp46) expression in glial cells in a time-dependent manner

Abstract

Maintaining the cholesterol homeostasis is essential for normal CNS functioning. The enzyme responsible for elimination of cholesterol excess from the brain is cholesterol 24-hydroxylase (Cyp46). Since cholesterol homeostasis is disrupted following brain injury, in this study we examined the effect of right sensorimotor cortex suction ablation on cellular and temporal pattern of Cyp46 expression in the rat brain. Increased expression of Cyp46 at the lesion site at all post injury time points (2, 7, 14, 28 and 45 days post injury, dpi) was detected. Double immunofluorescence staining revealed colocalization of Cyp46 expression with different types of glial cells in time-dependent manner. In ED1(+) microglia/macrophages Cyp46 expression was most prominent at 2 and 7 dpi, whereas Cyp46 immunoreactivity persisted in reactive astrocytes throughout all time points post-injury. However, during the first 2 weeks Cyp46 expression was enhanced in both GFAP(+) and Vim(+) astrocytes, while at 28 and 45 dpi its expression was mostly associated with GFAP(+) cells. Pattern of neuronal Cyp46 expression remained unchanged after the lesion, i.e. Cyp46 immunostaining was detected in dendrites and cell body, but not in axons. The results of this study clearly demonstrate that in pathological conditions, like brain injury, Cyp46 displayed atypical expression, being expressed not only in neuronal cells, but also in microglia and astrocytes. Therefore, injury-induced expression of Cyp46 in microglial and astroglial cells may be involved in the post-injury removal of damaged cell membranes contributing to re-establishment of the brain cholesterol homeostasis.

Cholesterol and ocular pathologies: focus on the role of cholesterol-24S-hydroxylase in cholesterol homeostasis

“…CYP46A1 expression would be an adaptive response of the retina to changes in cholesterol levels. Similar activation of CYP46A1 in microglia was already reported in the brain in response to injury (Smiljanic et al, 2010).…”

Expression profiles of cholesterol metabolism-related genes are altered during development of experimental autoimmune encephalomyelitis in the rat spinal cord

“…Previously, we and others have shown that activated macrophages/microglia express CYP46A1 in traumatic brain injury 26, 46 . Additionally, it was suggested that infiltrating macrophages express CYP46A1 during EAE 45 .…”

“…CYP46A1 expression was found in many types of neurons, where a majority of CYP46A1 expression was exclusively associated to neuronal somata, with lower levels found in dendrites 23, 26, 44, 56 . This study also revealed a strong CYP46A1 immunoreactivity in the neuronal somata in the grey matter at the onset and the end of EAE, which was lowered at the peak of disease probably due to neuronal degeneration.…”

“…Similarly, CYP46A1 positive astrocytes, surrounding the lesion site were detected after the hippocampal kainate injury 25 . In our previous study 26 , we have reported that traumatic brain injury induces the long-lasting upregulation of CYP46A1 protein expression at the lesion site, which was attributed to microglia and astrocytes in a time-dependent manner.…”

Histochemistry and cell biology: the annual review 2010

“…As so far only few studies demonstrated atypical Cyp46 expression in astrocytes under certain circumstances [e.g. human frontal cortex- (Brown et al 2004), and advanced Alzheimer disease- (Bogdanovic et al 2001)], Smiljanic et al (2010) were interested to study cellular and temporal pattern of Cyp46 expression in the context of traumatic brain injury (TBI), a widespread cause of death and major source of adult disability. Employing a rat TBI model the authors found longlasting neuronal and glial Cyp46 expression at the lesion site, indicating that TBI-induced production of damaged cell membranes elicits wide-spead Cyp46 expression to re-establish brain cholesterol homeostasis required for a glial scar formation.…”