Qiang Su1, Tian Li1, Pei-Feng He2, Xue-Chun Lu3, Qi Yu4, Qi-Chao Gao1, Zhao-Jun Wang1, Mei-Na Wu1, Dan Yang1, Jin-Shun Qi5. 1. Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. 2. Institute of Medical Data Sciences and School of Management, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. hepeifeng2006@126.com. 3. Department of Hematology, the Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China. luxuechun@126.com. 4. Institute of Medical Data Sciences and School of Management, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. 5. Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. jinshunqi2009@163.com.
Abstract
BACKGROUND: 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. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. METHODS: Novel 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. RESULTS: TSA 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. CONCLUSIONS: These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
BACKGROUND: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. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. METHODS: Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1transgenic 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. RESULTS:TSA 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/PS1mice. 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. CONCLUSIONS: These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Entities:
Keywords:
APP/PS1 mice; Albumin; Amyloid β clearance; Learning and memory; Microglia; Trichostatin A
Authors: R B DeMattos; K R Bales; D J Cummins; J C Dodart; S M Paul; D M Holtzman Journal: Proc Natl Acad Sci U S A Date: 2001-07-03 Impact factor: 11.205
Authors: B De Strooper; P Saftig; K Craessaerts; H Vanderstichele; G Guhde; W Annaert; K Von Figura; F Van Leuven Journal: Nature Date: 1998-01-22 Impact factor: 49.962
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