Abstract
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 β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ 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 Aβ aggregation and promoted the phagocytosis of Aβ oligomers.ConclusionsThese findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Highlights
Alzheimer’s disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure
We noticed that Trichostatin A (TSA) alone (WT + TSA) markedly elevated novel object recognition index” (NOI) compared to vehicle-treated WT mice (p < 0.001)
TSA reduced both amyloid β (Aβ) plaques and Aβ oligomers in the hippocampus, as well as Aβ levels in the plasma of amyloid precursor protein (APP)/ PS1 mice Given that Aβ plaque is one important neuropathological hallmark in AD brains [22], we firstly evaluated whether TSA affected Aβ plaques in the hippocampus of APP/PS1 mice by Thioflavin S (ThioS) staining and Aβ immunostaining (6E10)
Summary
Alzheimer’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. Alzheimer’s disease (AD), a chronic neurodegenerative disease, is the most common cause of dementia in elderly individuals. The imbalance between the production and clearance of Aβ has been considered as the major cause of excessive aggregation of neurotoxic Aβ in the brain [7, 8]. Since Aβ production and accumulation is an inevitable consequence in the progression of AD, targeting the clearance of Aβ in the brain of AD patients becomes a potential therapeutic strategy for AD. Many researchers reported their results on Aβ clearance, the detailed mechanisms underlying Aβ clearance are still not fully elucidated, and the drugs that could effectively remove Aβ remain to be further explored
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