Trichostatin A ameliorates Alzheimer's disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice

BackgroundAlzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms.MethodsNovel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS.ResultsTSA treatment not only reduced amyloid beta (A beta) plaques and soluble A beta oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of A beta pathology by TSA was attributed to the enhancement of A beta clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited A beta aggregation and promoted the phagocytosis of A beta oligomers.ConclusionsThese findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.