Dysregulated expression of tight junction proteins and compromise of blood-brain barrier (BBB) integrity are associated with pathological progression of HIV-1-associated neurocognitive disorders (HAND). Fibroblast growth factor-18 (FGF18), an important member of the fibroblast growth factor (FGF) family, has been considered a neuroprotectant with a wide range of physiological functions. However, the effects of FGF18 in HAND have not been reported previously. Here, we report that FGF18 expression was reduced in the cortex of mice challenged with HIV-1 Tat. Intracerebroventricular administration of FGF18 suppressed vascular inflammation in the cortex of HIV-1 Tat-challenged mice by inhibiting VCAM-1 and ICAM-1 expression. FGF18 alleviated BBB dysfunction induced by HIV-1 Tat through upregulating ZO-1 expression. Mechanistically, FGF18 prevented HIV-1 Tat-induced downregulation of Wnt-3a and β-catenin. We further demonstrate that FGF18 ameliorated HIV-1 Tat-induced cytotoxicity in bEnd.3 brain microvascular endothelial cells by reducing LDH and HMGB-1 release. Moreover, FGF18 protected the endothelial permeability of bEnd.3 cells and restored trans-endothelial electrical resistance (TEER) in cells challenged with HIV-1 Tat. Consistently, FGF18 prevented the reduction of ZO-1 expression as well as Wnt-3a/β-catenin levels in bEnd.3 cells challenged with HIV-1 Tat. Importantly, silencing of Wnt-3a abrogated the beneficial effects of FGF18 in increasing ZO-1 expression and reducing endothelial permeability, indicating that the protective effects of FGF18 are mediated by Wnt-3a/β-catenin signaling. We conclude that FGF18 may serve as an effective neuroprotective agent for the treatment of HAND.
Zhang et al. (Fri,) studied this question.