Inhibition of Fli‐1 attenuates inflammation, pericyte loss and cognitive deficits in Alzheimer’s disease

Abstract

AbstractBackgroundBrain pericytes maintain the integrity of the blood‐brain barrier (BBB) and facilitate the removal of amyloid β (Aβ) which is critical to healthy brain activity (Ethan et al., Brain Pathol., 24: 371‐386, 2014). Pericyte degeneration has been observed in brains from patients with Alzheimer’s disease (AD) and animal models (Jesse et al., Brain Pathol., 23: 303‐10, 2013; Wu et al., Aging (Albany NY), 11: 6120‐6133, 2019). Our previous data demonstrated that friend leukemia virus integration 1 (Fli‐1), an ETS transcription factor, regulates pericyte viability and vascular injury in murine sepsis (Li et al., J Infect Dis, 218: 1995‐2005, 2018); however, the role of Fli‐1 in AD remains unknown.MethodsFli‐1 levels and pericyte number were detected in postmortem brains from 21 patients with AD and 17 healthy controls, and in 5xFAD transgenic mice. Control or Fli‐1 antisense oligonucleotide Gapmers were injected into the hippocampus of 5xFAD mice at 3 and 4.5 months of age. Pericyte number, inflammatory mediators, Aβ deposition, BBB function and cognitive deficits were evaluated at 6 months of age. Human brain pericytes were transfected with control or Fli‐1 antisense Gapmers for 48 h and cultured with or without freshly aggregated Aβ40 for 7 consecutive days. Cell viability and apoptosis were detected.ResultsWe demonstrated that Fli‐1 expression was increased in postmortem brains from a cohort of human AD donors and in 5xFAD mice, which corresponded with a decreased pericyte number, elevated inflammatory mediators, and increased Aβ accumulation as compared to cognitively normal individuals and WT mice, respectively. Antisense oligonucleotide Fli‐1 Gapmer administrated via intrahippocampal injection decelerated pericyte loss, reduced inflammatory responses, ameliorated cognitive deficits, improved BBB dysfunction, and decreased Aβ deposition in 5xFAD mice. Fli‐1 Gapmer‐mediated inhibition of Fli‐1 protected against Aβ accumulation induced human brain pericyte apoptosis in vitro.ConclusionThese composite results indicate that Fli‐1 contributes to pericyte loss, inflammatory response, Aβ deposition, vascular dysfunction and cognitive decline, and suggest that suppression of Fli‐1 may represent a novel therapeutic strategy for AD.